Synthesis Process Of Ormetoprim Optimization Study

5-（4,5-dimethoxy-2-methylbenzyl）pyrimidine-2,4-diamine（also known as orme-toprim）was a kind of antibacterial synerists,which could enhance the efficacy of antibacterial agents as a companion.So farormetoprim had been widely used in the culture industry and attracted a massive attention.In this thesis,it had summarized all of the known systhesis routes of ormetoprim,meanwhile,based on their advantages and disadvantages,an improved synthesis route of ormetoprim was introduced.The improved route comprised methylation,oxybro-mination,methoxylation,Vilsmeier-Haack reaction,dehydration synthesis,isomerize-tion and addition reaction,cyclization and started with p-methylphenol as the starting material.Some advantages of it had shown below:a.A green chemistry consideration,hydrobromic acid/oxygen/sodium nitrite as green reagents was introduced in the second step.b.A novel reagents mixture,DMF&oxalyl chloride was used for the fourth step,the Vilsmeier-Haack reaction with the brand-new reagent method.Telescoped three steps,dehydration,isomerization and addition reaction,into one single step.The breakthrough impacts positively the process,such as higher yield（74.6%much higher than literature 66.6%）,purity（above 99.5%）,a system of material recycling,the material cost（25.68%cut off）,lower waste,and greener&more eviromentally friendly.The new route had been successfully proved with three batches industrial production of 100 kg.The structure of ormetoprim was also confirmed by MS,¹H-NMR,¹³C-NMR,DEPT-135°,¹H,¹H-COSY,¹H,¹³C-HSQC and¹H,¹³C-HMBC spectra.The optimized process conditions for each step reation were shown below.（1）For the methylation reaction,the mole ratio of p-methylphenol to TBAB to DMC to K₂CO₃ was 1:0.5:10:0.75,the optimal reaction condition was ranged in90⁹5℃with a 5-hour reaction time.（2）For the oxybromination reaction,the optimal conditions were that the mole ratio of p-methyl anisole to hydrobromic acid to sodium nitrite was 1:1.1:0.03,60%methanol aqueous solution used as the solvent,the reaction temperature was 20²5℃with a 4-hour reaction time.（3）For the methoxylation,the optimal conditions were that the mole ratio of3-bromo-4-methoxy-1-methylbenzene to cuprous chloride to sodium methoxide was1:0.1:2,methanol as solvent,it was reflux with a 16-hour reaction time.（4）For the Vilsmeier-Haack reaction,the optimal conditions were that the mole ratio of 3,4-dimethoxy toluene to oxalyl chloride was 1.0:3.0,3 fold of DMF in weight to the raw material,it was agitated around 90⁹5℃for 6 hours.（5）For the dehydration synthesis reaction,the optimal conditions were that the mole ratio of 4,5-dimethoxy-2-methylbenzaldehyde to acrylonitrile to sodium metho-xide was 1.0:2.0:4.0,the best reaction temperature was around 25³0℃for 16 hours;Furthermore,for the isomerization and addition reaction,the optimal conditions were that using 5 fold weight of DMF to the raw material as the solvent,the reaction temperature was set around 80⁸5℃and warmed for 3 hours;Meanwhile,for the cyclization,the optimal conditions were that adjusting the dose of guanidine to 1equivalence,it was warmed at 110¹15℃for 3 hours.In summary,the novel method had a major advantage that telescope the dehydration synthesis reaction,isomerization and addition reaction,cyclization together as a“one-pot method”,and ormetoprim could be obtained directly from the crystallization of DMF reaction solution with a moreeasily operation and higher yield.