Skip to main content


Log in

Continuous synthesis of N-(3-Amino-4-methylphenyl)benzamide and its kinetics study in microflow system

  • Full Paper
  • Published:
Journal of Flow Chemistry Aims and scope Submit manuscript


N-(3-Amino-4-methylphenyl)benzamide (1) is a crucial building blocks of many drug candidates. In this paper, a continuous flow microreactor system was developed to synthesize 1 and determine intrinsic reaction kinetics parameters. By screening the acylating reagents and reaction conditions, 1 was obtained by the selective acylation of 4-methylbenzene-1,3-diamine (2) with benzoic anhydride (3). Since the two amine groups in 2 are in different chemical environments, parallel by-products and serial by-products coexist, which makes the selective monoacylation process relatively complicated. To reveal the reaction process clearly, reaction rate constants and their 95% confidence intervals, activation energies, pre-exponential factors were acquired by kinetics study in microflow system. The established kinetic model can calculate the selectivity and conversion of the acylation reaction, which are in good agreement with the experimental results. Subsequently, the kinetic model was used to optimize reaction conditions, as a result, 1 was synthesized in the microreactor with a yield of 85.7% within 10 min.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others


  1. Martz KE, Dorn A, Baur B, Schattel V, Goettert MI, Mayer-Wrangowski SC, Rauh D, Laufer SA (2012) Targeting the hinge glycine flip and the activation loop: novel approach to potent p38alpha inhibitors. J Med Chem 55(17):7862–7874.

    Article  CAS  PubMed  Google Scholar 

  2. Wrobleski ST, Lin S, Hynes J Jr, Wu H, Pitt S, Shen DR, Zhang R, Gillooly KM, Shuster DJ, Mcintyre KW, Doweyko AM, Kish KF, Tredup JA, Duke GJ, Sack JS, Mckinnon M, Dodd J, Barrish JC, Schieven GL, Leftheris K (2008) Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors. Bioorg Med Chem Lett 18(8):2739–2744.

    Article  CAS  PubMed  Google Scholar 

  3. Ren PD, Gray NS, Wang X, Zhang G Compounds and compositions as protein kinase inhbitors. 2006: WO 2006101783A2

  4. Kim HJ, Cho HJ, Kim H, El-Gamal MI, Oh CH, Lee SH, Sim T, Hah JM, Yoo KH (2012) New diarylureas and diarylamides possessing acet(benz)amidophenyl scaffold: design, synthesis, and antiproliferative activity against melanoma cell line. Bioorg Med Chem Lett 22(9):3269–3273.

    Article  CAS  PubMed  Google Scholar 

  5. Brown DS, Brown GR, Cohen P (1999) Preparation of N,N’-diacyl-1,3-benzenediamines for the treatment of diseases mediated by cytokines, vol 9915164A1. WO

  6. Munoz B, Bastos CM, Parks D, Kombo D (2017) Preparation of quinolines and related compounds, compositions, and methods for modulating CFTR. WO2017062581A, p 1

  7. Guidi M, Seeberger PH, Gilmore K (2020) How to approach flow chemistry. Chem Soc Rev 49(24):8910–8932.

    Article  CAS  PubMed  Google Scholar 

  8. Sui JS, Yan JY, Liu D, Wang K, Luo GS (2020) Continuous synthesis of nanocrystals via flow chemistry technology. Small 16(16):1902828–1902850.

    Article  CAS  Google Scholar 

  9. Britton J, Raston CL (2017) Multi-step continuous-flow synthesis. Chem Soc Rev 46(5):1250–1271.

    Article  CAS  PubMed  Google Scholar 

  10. Hughes DL (2020) Applications of flow chemistry in the pharmaceutical industry—highlights of the recent patent literature. Org. Process Res Dev 24(10):1850–1860.

    Article  CAS  Google Scholar 

  11. Jensen KF (2017) Flow chemistry-Microreaction technology comes of age. AIChE J 63(3):858–869.

    Article  CAS  Google Scholar 

  12. Rossetti I, Compagnoni M (2016) Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry. Chem Eng J 296:56–70.

    Article  CAS  Google Scholar 

  13. Gutmann B, Cantillo D, Kappe CO (2015) Continuous-flow technology-a tool for the safe manufacturing of active pharmaceutical ingredients. Angew Chem Int Ed Engl 54(23):6688–6728.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang J, Yan S, Yuan D, Alici G, Nguyen NT, Ebrahimi Warkiani M, Li W (2016) Fundamentals and applications of inertial microfluidics: a review. Lab Chip 16(1):10–34.

    Article  CAS  PubMed  Google Scholar 

  15. Bogdan AR, Dombrowski AW (2019) Emerging trends in flow chemistry and applications to the pharmaceutical industry. J Med Chem 62(14):6422–6468.

    Article  CAS  PubMed  Google Scholar 

  16. Bloemendal VRLJ, Janssen MaCH, Van Hest JCM, Rutjes FPJT (2020) Continuous one-flow multi-step synthesis of active pharmaceutical ingredients. React Chem Eng 5(7):1186–1197.

    Article  CAS  Google Scholar 

  17. Hartman RL, Jensen KF (2009) Microchemical systems for continuous-flow synthesis. Lab Chip 9(17):2495–2507.

    Article  CAS  PubMed  Google Scholar 

  18. Shi XQ, Liu SE, Duanmu CS, Shang MJ, Qiu M, Shen C, Yang Y, Su YH (2021) Visible-light photooxidation of benzene to phenol in continuous-flow microreactors. Chem Eng J 420:129976–129987.

    Article  CAS  Google Scholar 

  19. Xie Y, Huang GM, Wang YJ, Yan ZR, Wang X, Huang J, Gao MT, Fei WY, Luo GS (2020) Synthesis of piperacillin with low impurity content using a new three-feed membrane dispersion microreactor. Chem Eng J 387:124178–124186.

    Article  CAS  Google Scholar 

  20. Fu WC, Jamison TF (2019) Modular continuous flow synthesis of imatinib and analogues. Org Lett 21(15):6112–6116.

    Article  CAS  PubMed  Google Scholar 

  21. Ziegler RE, Desai BK, Jee JA, Gupton BF, Roper TD, Jamison TF (2018) 7-Step flow synthesis of the HIV integrase inhibitor dolutegravir. Angew Chem Int Ed Engl 57(24):7181–7185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Szeto J, Vu V-A, Malerich JP, Collins N (2018) Multi-step continuous flow synthesis of fluconazole. J Flow Chem 9(1):35–42.

    Article  CAS  Google Scholar 

  23. Mancino V, Cerra B, Piccinno A, Gioiello A (2018) Continuous flow synthesis of 16-dehydropregnenolone acetate, a key synthon for natural steroids and drugs. Org Process Res Dev 22(5):600–607.

    Article  CAS  Google Scholar 

  24. Azad MA, Osorio JG, Brancazio D, Hammersmith G, Klee DM, Rapp K, Myerson A (2018) A compact, portable, re-configurable, and automated system for on-demand pharmaceutical tablet manufacturing. Int J Pharm 539(1–2):157–164.

    Article  CAS  PubMed  Google Scholar 

  25. Cole KP, Groh JM, Johnson MD, Burcham CL, Campbell BM, Diseroad WD, Heller MR, Howell JR, Kallman NJ, Koenig TM, May SA, Miller RD, Mitchell D, Myers DP, Myers SS, Phillips JL, Polster CS, White TD, Cashman J, Hurley D, Moylan R, Sheehan P, Spencer RD, Desmond K, Desmond P, Gowran O (2017) Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science 356(6343):1144–1150.

    Article  CAS  PubMed  Google Scholar 

  26. Huang JP, Sang FN, Luo GS, Xu JH (2017) Continuous synthesis of Gabapentin with a microreaction system. Chem Eng Sci 173:507–513.

    Article  CAS  Google Scholar 

  27. Li GX, Liu S, Dou XY, Wei HL, Shang MJ, Luo ZH, Su YH (2020) Synthesis of adipic acid through oxidation of K/A oil and its kinetic study in a microreactor system. AIChE J 66(9):16289–16300.

    Article  CAS  Google Scholar 

  28. Xu QL, Fan HC, Yao HM, Wang DH, Yu HW, Chen BB, Yu ZQ, Su WK (2020) Understanding monoacylation of symmetrical diamines: A kinetic study of acylation reaction of m-phenylenediamine and benzoic anhydride in microreactor. Chem Eng J 398:125584–125593.

    Article  CAS  Google Scholar 

  29. Yao Z, Xu X, Dong YL, Liu X, Yuan B, Wang K, Cao K, Luo GS (2020) Kinetics on thermal dissociation and oligomerization of dicyclopentadiene in a high temperature & pressure microreactor. Chem Eng Sci 228:115892–115898.

    Article  CAS  Google Scholar 

  30. Zhang H, Yu ZY, Gu T, Xiang L, Shang MJ, Shen C, Su YH (2020) Continuous synthesis of 5-hydroxymethylfurfural using deep eutectic solvents and its kinetic study in microreactors. Chem Eng J 391.

  31. Nagy KD, Shen B, Jamison TF, Jensen KF (2012) Mixing and dispersion in small-scale flow systems. Org. Process Res Dev 16(5):976–981.

    Article  CAS  Google Scholar 

  32. Wilke CR, Chang P (1955) Correlation of diffusion coefficients in dilute solutions. AIChE J 1:264–270.

    Article  CAS  Google Scholar 

  33. Xu QL, Liu JM, Yao HM, Zhao JY, Wang ZK, Liu JL, Zhou JD, Yu ZQ, Su WK (2021) Insight into fundamental rules of phenylenediamines selective monoacylation by the comparisons of kinetic characteristics in microreactor. Bull Korean Chem Soc 42(10):1336–1344.

    Article  CAS  Google Scholar 

Download references


We are grateful to High-Level Talent Project of West Anhui University (WGKQ2022030), Key Project of Natural Science Research in Universities of Anhui Province (KJ2021A0957), Natural Science Foundation of Anhui Province (2008085QB96), Postdoctoral Science Foundation of Anhui Province (2020B454) for financial support.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Qilin Xu or Zhiqun Yu.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, Q., Li, G., Zhu, F. et al. Continuous synthesis of N-(3-Amino-4-methylphenyl)benzamide and its kinetics study in microflow system. J Flow Chem 12, 317–325 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: