Syntheses of antibacterial 2,4-diamino-5-benzylpyrimidines. Ormetoprim and trimethoprim
作者:Percy S. Manchand、Perry Rosen、Peter S. Belica、Gloria V. Oliva、Agostino V. Perrotta、Harry S. Wong
DOI:10.1021/jo00039a006
日期:1992.6
A general and mild method for the synthesis of 2,4-diamino-5-benzylpyrimidines was achieved by the Friedel-Crafts reaction between 2-(methoxymethylene)-3-methoxypropanenitrile (10) and an activated aromatic substrate followed by treatment with guanidine. The method is illustrated by a synthesis of ormetoprim (2) in 75% overall yield from 3,4-dimethoxytoluene (12). Efficient syntheses of trimethoprim (1) and 2 were also accomplished via prior base-catalyzed 1,3-prototropic isomerization of cinnamonitriles 19 and 20, respectively, followed by condensation with guanidine. 12 was prepared from 3-bromo-4-methoxytoluene by a Cu(I)-catalyzed displacement of bromine by methoxide and 4,5-dimethoxy-2-methylbenzaldehyde was obtained from 12 in 87% yield by a pyridine-catalyzed Vilsmeier reaction using DMF-POCl3.