- Syntheses of Antibacterial 2,4-Diamino-5-benzylpyrimidines. Ormetoprim and Trimethoprim
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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 75percent 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 87percent yield by a pyridine-catalyzed Vilsmeier reaction using DMF-POCl3.
- Manchand, Percy S.,Rosen, Perry,Belica, Peter S.,Oliva, Gloria V.,Perrotta, Agostino V.,Wong, Harry S.
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p. 3531 - 3535
(2007/10/02)
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- Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines
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2,4-Diaminopyrimidines bearing a substituted benzyl group in position-1 are prepared from the correspondingly substituted α-alkoxymethylcinnamonitrile by treatment of the latter with an alkali metal alkoxide in mono-methyl ether of ethylene glycol and subsequently reacting the resulting reaction mixture with guanidine.
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