Guanidine Trimethoprim

Trimethoprim has also been synthesized by condensing 3,4,5-trimethoxybenzaldehyde with malonic acid dinitrile in a Knoevenagel reaction, which forms the derivative (33.1.53), which is partially reduced to the enamine (33.1.54) by hydrogen using a palladium on carbon catalyst, which upon being reacted with guanidine is transformed into trimethoprim [52,53]. 

Condensation with ethyl formate (HC02Et) and cyclization with guanidine gives the pyrimidine ring system but with an OH instead of the required amino group. Aromatic nucleophilic substitution in the pyrimidone style from Chapter 43 gives trimethoprim. 

Since then major improvements have taken place in the technology front particularly in China and India where this drug is still very popular. For instance, considerable work has been carried out by the Department of Energy Utilization and Chemical Engineering, China University of Mining and Technology. They have reported that efficient synthesis of trimethoprim from 3,4,5-TMBA was accomplished by condensation with methanolic sodium methoxide, methanol and acrylonitrile via prior base-catalyzed 1,3-prototropic isomerization of cinnamonitrile converted into the enol ether, followed by addition with methanol at 90°C and cyclocondensation directly with guanidine in DMSO at 110°C with the removal of methanol. 

It was established that the reaction between 45 and 3,4,5-trimethoxybenzaldehyde 46 required cooling in an ice bath in order to obtain reproducible results and a cleaner product, and hence, microwave irradiation was not utilized in this step. Intermediate 47, thus obtained using conventional methods, was used for the synthesis of 43 under microwave conditions without further purification. Reaction of 47 with a large excess of guanidine under microwave irradiation for 30 min at 140°C afforded trimethoprim 43 in 40% yield, assessed by high-performance liquid chromatography (HPLC). Further optimization of these reaction conditions did not increase the yield of the product. 

It is eomparatively a shorter course of reaetion whereby cinnamonitrile is prepared by the interaetion of 3, 4, 5-trimethoxy-benzaldehyde with 3-ethoxy propionitrile with the elimination of a mole of water. The resulting product on treatment with guanidine affords the formation of trimethoprim directly. 

Eqn. (c) shows the cyclization of intermediate (II) with guanidine, in methanol, to yield the desired product, trimethoprim, (III) with the elimination of water. 

A similar method has been applied in the synthesis of Trimelhoprim [738-70-5], a chemotherapeutic, antibacterial API (reaction of 3,4,5-trimethoxyberi2ylcyanoacetic acid with DMF and phosgene, followed by reaction with guanidine, leads directly to trimethoprim) [158,159]. 

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