Propanamide, N-(4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-

Synthesis

1538-75-6

7355-55-7

137281-08-4

The general procedure for the synthesis of N-(4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide from pivalic anhydride and 2-amino-4-hydroxypyrrolo[2,3-d]pyrimidine was as follows: firstly, a pivaloylation reaction was carried out on the 2-amino portion of the pyrrolo[2,3-b]pyrimidine 8 to give compound 9 in the yield of 95%. This step is designed to decrease the polarity and increase the solubility of the compound. The product 9 can be precipitated directly by adding hexane and ethyl acetate (5:1, v/v) to the reaction mixture.Subsequently, Mannich reaction was carried out on compound 9 to give compound 10 in 70-80% yield. During this process, a buffer was formed using KOAc to stabilize the pH of the phosphate protecting groups. Next, compound 10 was converted to compound 11 in 90% yield by a Pd-catalyzed debenzylation reaction. None of the above steps required chromatographic purification. For compound 10, acetone was added and filtered after removing the solvent, and the filtrate was distilled to give a semi-solid crude 10, which can be used directly in the next step of the reaction. For compound 11, after filtration to remove the Pd/C and evaporation of the solvent, the resulting residue was washed with acetone to give the pure product 11. Compound 11a was analyzed by HMBC spectroscopy and three JCH signals and two JCH signals were observed (not shown). To determine the regioselectivity of the Mannich reaction, compound 11a was analyzed by NOESY and HMBC. Weak NOE signals between N7-H and 6'-H were observed, possibly due to quadrupolar N7-H and 3J(C4-H5) signals in NOESY and 3J(C5 or C9-H3 or H7) signals observed in HMBC (not shown), and these results confirmed that compound 11a has an aminomethyl substitution at the 6-position.

References