An Improved One-Pot Procedure for Preparation Of N,N -Diethyl-m-Toluamide from m-Toluic Acid
Keywords:
m-toluic acid, N, N-diethyl-m-toluamide, ingredient, insects repellent.Abstract
Introduction: Recent statistics have shown that there are hundreds of diseases caused by insects that have a significant impact on human health and they are often fatal. Mosquitoes cause about 10 diseases, most notably malaria, dengue fever and zika fever. N,N-diethyl-m-toluamide (1, DEET) or N,N-diethyl-m-methylbenzamide was globally approved under brand names m-Dephene, Detamide, Flypel as one of the most prominent agents for preparation of insect repellants.Objectives: To present an enhanced method for synthesis of N,N'-diethyl- m-toluamide which can be introduced to industrial scale.
Method: The input materials: m-toluic acid has been activated with thionyl chloride to create the intermediate product, m-toluoyl chloride. This product then was reacted with diethylamine in order to produce DEET. This method has been improved the factors affecting the synthesis of DEET.
Results: DEET was successfully synthesized using well known materials with high efficiency and purity. During research all the by-products and waste materials in the reaction are highly water-soluble, therefore the final product was obtained at pharmaceutical requirement without further purification. The analytical data has shown that DEET was collected at a very high yield in the range of 96-98%, purity (HPLC): 95.5-97.6%. The structure of DEET was determined by model spectroscopies MS, and NMR.
Conclusions: An improved procedure for the synthesis of N,N-diethyl-m -toluamide (DEET) or N,N-diethyl-m-methylbenzamide is established where the use of all reagents was optimized in suitable amount to apply in industrial production.
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References
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10. Xie S, Lin H, Liu D, Shi C, Li L, Shen B, Zhang L, inventors; Guangzhou Liby Enterprise Group Co Ltd, titular. Mite-resistant fabric care composite. CN Patent 104988725A. 2015 Oct 21
11. Habeck JC, Diop L, Dickman M. Synthesis of N,N-Diethyl-3-methylbenzamide (DEET): Two Ways to the Same Goal, Journal of Chemical Education. 2010; 87(5):528-9 . DOI: 10.1021/ed800169h
12. Ellis LC, Kise MA, inventors; Hoechst Celanese Chemical Co Virginia Chemicals Inc, titular. Process for the manufacture of N,N-Diethyl-m-Toluamide by Aqueous Caustic Procedure. US Patent 3870756A. 1975 Mar 11
13. Nery MS, Ribeiro RP, Lopes CC, Lopes RSC. Niobium pentachloride promoted conversion of carboxylic acids to carboxamides: Synthesis of the 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloid structures, Synthesis. 2003; 2: 272-6. DOI: 10.1055/s-2003-36823
14. Chaysripongkul S, Pluempanupat W, Jang DO, Chavasiri W. Application of Cl3CCONH2/PPh3 towards the synthesis of bioactive amides, Bulletin of the Korean Chemical Society. 2009; 30(9):2066-70. DOI: 10.5012/bkcs.2009.30.9.2066
15. Phalen WL, inventors; Hercules Powder Co, titular. Preparation of N,N -dethyltoluamides. US Patent 2991310A. 1961 Jul 04
16. Seavill PW, Wilden JD. The preparation and applications of amides using electrosynthesis, Green Chemistry. 2020; 22:7737-59. DOI: 10.1039/d0gc02976a
2. Windheuser JJ, Haslam JL, Caldwell L, Shaffer RD, The Use of N,N -Diethyl-m-Toluamide to Enhance Dermal and Transdermal Delivery of Drugs, Journal of Pharmaceutical Sciences. 1982; 71(11):1211-13.DOI: 10.1002/jps.2600711107
3. Gertler SI, inventors; National Aeronautics and Space Administration NASA US Department of Agriculture USDA, titular . N,N-diethylbenzamide as an insect repellent. US Patent 2408389A. 1994 Sep 04.
4. Pattabiraman VR, Bode JW. Rethinking amide bond synthesis, Nature. 2011; 480: 471-9. DOI: 10.1038/nature10702
5. Dunetz JR, Magano J, Weisenburger GA. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals, Organic Process Research & Development. 2016; 20:140-77. DOI: 10.1021/op500305s
6. Zhu YP, Sergeyev S, Franck P, Orru RVA, Maes BUW. Amine Activation: Synthesis of N‑(Hetero)arylamides from Isothioureas and Carboxylic Acids, Organic letters. 2016; 18(18): 4602-05. DOI: 10.1021/acs.orglett.6b02247
7. Zhu YP, Mampuys P, Sergeyev S, Ballet S, Maes BUW. Amine Activation: N-Arylamino Acid Amide Synthesis from Isothioureas and Amino Acids, Advanced Synthesis & Catalysis. 2017; 359(14): 2481-9. DOI: 10.1002/adsc.201700134
8. Knoess HP, Neeland EG. A Modified Synthesis of Insect Repellent DEET, Journal of Chemical Education. 1998; 75(10):1267-8. DOI: 10.1021/ed075p1267
9. Zhuang Z, Hu ZP, Liao WW. Asymmetric Synthesis of Functionalized Dihydronaphthoquinones Containing Quaternary Carbon Centers via a Metal-Free Catalytic Intramolecular Acylcyanation of Activated Alkenes , Organic Letters. 2014; 16(12):3380-3. DOI: 10.1021/ol501427h
10. Xie S, Lin H, Liu D, Shi C, Li L, Shen B, Zhang L, inventors; Guangzhou Liby Enterprise Group Co Ltd, titular. Mite-resistant fabric care composite. CN Patent 104988725A. 2015 Oct 21
11. Habeck JC, Diop L, Dickman M. Synthesis of N,N-Diethyl-3-methylbenzamide (DEET): Two Ways to the Same Goal, Journal of Chemical Education. 2010; 87(5):528-9 . DOI: 10.1021/ed800169h
12. Ellis LC, Kise MA, inventors; Hoechst Celanese Chemical Co Virginia Chemicals Inc, titular. Process for the manufacture of N,N-Diethyl-m-Toluamide by Aqueous Caustic Procedure. US Patent 3870756A. 1975 Mar 11
13. Nery MS, Ribeiro RP, Lopes CC, Lopes RSC. Niobium pentachloride promoted conversion of carboxylic acids to carboxamides: Synthesis of the 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloid structures, Synthesis. 2003; 2: 272-6. DOI: 10.1055/s-2003-36823
14. Chaysripongkul S, Pluempanupat W, Jang DO, Chavasiri W. Application of Cl3CCONH2/PPh3 towards the synthesis of bioactive amides, Bulletin of the Korean Chemical Society. 2009; 30(9):2066-70. DOI: 10.5012/bkcs.2009.30.9.2066
15. Phalen WL, inventors; Hercules Powder Co, titular. Preparation of N,N -dethyltoluamides. US Patent 2991310A. 1961 Jul 04
16. Seavill PW, Wilden JD. The preparation and applications of amides using electrosynthesis, Green Chemistry. 2020; 22:7737-59. DOI: 10.1039/d0gc02976a
Published
2022-11-06
How to Cite
1.
Duc TP, Van TN, Thu PB, Dinh CP, Le DV, Binh DV. An Improved One-Pot Procedure for Preparation Of N,N -Diethyl-m-Toluamide from m-Toluic Acid. Rev Cubana Med Milit [Internet]. 2022 Nov. 6 [cited 2025 Apr. 30];51(4):e02202154. Available from: https://revmedmilitar.sld.cu/index.php/mil/article/view/2154
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