Practical Preparation of Trimethoprim: A Classical Antibacterial Agent

Abstract

An efficient, simple, and mild preparation of the classical antibacterial agent trimethoprim (1) was achieved in 85% overall yield from 3,4,5-trimethoxybenzaldehyde (2). First, the addition of propenenitrile (3) with dimethylamine almost quantitatively afforded 3-dimethylaminopropanenitrile (7). Then, by condensation of 7 with 2 as well as the continuous replacement of 3-dimethylamino group with aniline in situ, the key intermediate 3-anilino-2-(3,4,5-trimethoxybenzyl)propenenitrile (9) was obtained in an excellent yield of 91% with a one-pot procedure. Finally, the cyclization of 9 with guanidine nitrate furnished 1 in yields as good as 95% in the presence of the excessive sodium methoxide.

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GRAPHICAL ABSTRACT

Keywords:

• Antibacterial agent
• highly effective preparation
• trimethoprim
• 3,4,5-trimethoxybenzaldehyde

ACKNOWLEDGMENTS

We thank the National Natural Science Foundation of China (Project No. 21176074) and Shandong Haoyuan Co. Ltd. for financial support.