Journal of Flow Chemistry

, Volume 8, Issue 3–4, pp 129–138 | Cite as

Continuous preparation for rifampicin

  • Xin Li
  • Zhuang Liu
  • Hao Qi
  • Zheng Fang
  • Siyu Huang
  • Shanshan Miao
  • Kai Guo
Full Paper


To reduce the cost and improve the efficiency for rifampicin preparation, a continuous flow synthesis of rifampicin starting from rifamycin S and tert-butylamine was studied in a microreactor. Two reaction steps and one purification step were coupled in a microreactor, and rifampicin was obtained with 67% overall yield. This method used 25% less 1-amino-4-methyl piperazine and got 16% higher overall yield without changing solvent and purification process between steps. This method has a good potential for further industrial application.


Continuous flow synthesis Coupling of reaction and separation Rifampicin preparation 



Authors acknowledges the funding from The jiangsu synergetic innovation center for advanced bio-manufacture (XTE1852), The National Key Research and Development Program of China (2016YFB0301501), National Natural Science Foundation of China (21522604), National Natural Science Foundation of China (U1463201), The National Natural Science Foundation of China (21776130), The jiangsu synergetic innovation center for advanced bio-manufacture (XTE1821), The jiangsu synergetic innovation center for advanced bio-manufacture (XTE1802).

Supplementary material

41981_2018_17_MOESM1_ESM.docx (314 kb)
ESM 1 (DOCX 313 kb)


  1. 1.
    Maggi CRPN, Ballotta R, Senst P (1966) Rifampicin: a new orally active rifamycin. Chemotherapia 11:8Google Scholar
  2. 2.
    Anonymous (1973) Analytical profiles of drug substances. Academic Press, New York and LondonGoogle Scholar
  3. 3.
    E. A. Anacleto Gianantonio, U. S. P. Office, Ed. (United States, 1970), vol. US 3542762Google Scholar
  4. 4.
    Bruzzese T (Holco investment Inc USA, 1979)Google Scholar
  5. 5.
    Leonardo Marsili CP, U. S. P. Office, Ed. (Current: Gruppo Lepetit SpA ( original: ARCHIFAR IND CHIM TRENTINO), Italy, 1975), vol. US3925366Google Scholar
  6. 6.
    Leonardo Marsili CP, U. S. P. Office, Ed. (Archifar Industrie Chimiche del Trentina S.p.A., Italy, 1976), vol. 3963705Google Scholar
  7. 7.
    Burke WJ, Murdock KC, Ec G (1954) Condensation of hydroxyaromatic compounds with formaldehyde and primary aromatic amines. J. Am. Chem. Soc. 76:1677–1679CrossRefGoogle Scholar
  8. 8.
    Burke WJ, Kolbezen MJ, Stephens CW (1952) Condensation of naphthols with formaldehyde and primary amines1. J. Am. Chem. Soc. 74:3601–3605CrossRefGoogle Scholar
  9. 9.
    Burke WJ, Weatherbee C (1950) 3,4-Dihydro-1,3,2H-Benzoxazines. Reaction of polyhydroxybenzenes with N-Methylolamines1. J. Am. Chem. Soc. 72:4691–4694CrossRefGoogle Scholar
  10. 10.
    Burke WJ (1949) 3,4-Dihydro-1,3,2H-Benzoxazines. Reaction of p-substituted phenols with N,N-Dimethylolamines. J. Am. Chem. Soc. 71:609–612CrossRefGoogle Scholar
  11. 11.
    四川抗菌素工业研究所半合成抗菌素研究室, 甲哌力复霉素生产工艺改革, 抗菌素, 1978, 02, 7–13Google Scholar
  12. 12.
    上海第五制药厂, 甲哌力复霉素合成新工艺——噁嗪路线, 医药工业, 1978, 10, 20–21Google Scholar
  13. 13.
    Fukang Lu JY, Xiaoyuan Liao (1985) Paper presented at the 第四次全国抗生素学术会议, Guilin, ChinaGoogle Scholar
  14. 14.
    Judit Némethné-Sóvágó MB (2014) Microreactors: a new concept for chemical synthesis and technological feasibility. Mater Sci Eng 39:89–101Google Scholar
  15. 15.
    Makarshin LL, Pai ZP, Parmon VN (2016) Microchannel systems for fine organic synthesis. Russ. Chem Rev 85:139–155CrossRefGoogle Scholar
  16. 16.
    Wang K, Li L, Xie P, Luo G (2017) Liquid-liquid microflow reaction engineering. React Chem Eng 2:611–627CrossRefGoogle Scholar
  17. 17.
    Zhang J, Wang K, Teixeira AR, Jensen KF, Luo G, in Annual review of chemical and biomolecular engineering, Vol 8, J. M. Prausnitz, Ed. (2017), vol. 8, pp. 285–305Google Scholar
  18. 18.
    Tanimu A, Jaenicke S, Alhooshani K (2017) Heterogeneous catalysis in continuous flow microreactors: a review of methods and applications. Chem. Eng. J. 327:792–821CrossRefGoogle Scholar
  19. 19.
    Mizuno K, Nishiyama Y, Ogaki T, Terao K, Ikeda H, Kakiuchi K (2016) Utilization of microflow reactors to carry out synthetically useful organic photochemical reactions. J Photochem Photobiol C: Photochem Rev 29:107–147CrossRefGoogle Scholar
  20. 20.
    Gordon CP (2018) The renascence of continuous-flow peptide synthesis - an abridged account of solid and solution-based approaches. Org Biomol Chem 16:180–196CrossRefGoogle Scholar
  21. 21.
    Das S, Srivastava VC (2016) Microfluidic-based photocatalytic microreactor for environmental application: a review of fabrication substrates and techniques, and operating parameters. Photochem Photobiol Sci 15:714–730CrossRefGoogle Scholar
  22. 22.
    Ma H, Bai Y, Li J, Chang Y-x (2018) Screening bioactive compounds from natural product and its preparations using capillary electrophoresis. Electrophoresis 39:260–274CrossRefGoogle Scholar
  23. 23.
    Fanelli F, Parisi G, Degennaro L, Luisi R (2017) Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis. Beilstein J Org Chem 13:520–542CrossRefGoogle Scholar
  24. 24.
    Sun B, Jiang J, Shi N, Xu W (2016) Application of microfluidics technology in chemical engineering for enhanced safety. Process Saf Prog 35:365–373CrossRefGoogle Scholar
  25. 25.
    Li X, Chen A, Zhou Y, Huang L, Fang Z, Gan H, Guo K (2015) Two-stage flow synthesis of coumarin via O-Acetylation of Salicylaldehyde. J Flow Chem 5:82–86CrossRefGoogle Scholar
  26. 26.
    He W, Fang Z, Tian Q, Shen W, Guo K (2016) Tandem, effective continuous flow process for the epoxidation of cyclohexene. Ind Eng Chem Res 55:1373–1379CrossRefGoogle Scholar
  27. 27.
    Ji D, Fang Z, He W, Zhang K, Luo Z, Wang T, Guo K (2015) Synthesis of soy-polyols using a continuous microflow system and preparation of soy-based polyurethane rigid foams. ACS Sustain Chem Eng 3:1197–1204CrossRefGoogle Scholar
  28. 28.
    He W, Fang Z, Tian Q, Ji D, Zhang K, Guo K (2015) Two-stage continuous flow synthesis of epoxidized fatty acid methyl esters in a micro-flow system. Chem Eng Process 96:39–43CrossRefGoogle Scholar
  29. 29.
    He W, Fang Z, Ji D, Chen K, Wan Z, Li X, Gan H, Tang S, Zhang K, Guo K (2013) Epoxidation of soybean oil by continuous micro-flow system with continuous separation. OrgProcess Res Dev 17:1137–1141CrossRefGoogle Scholar
  30. 30.
    Zhu YDKCaJ (2006) Effects of the medium pH values on rifamycin oxazino cyclic reaction. Chin J Antibiot 31(10):3Google Scholar
  31. 31.
    Reverchon E, De Marco I, Della Porta G (2002) Rifampicin microparticles production by supercritical antisolvent precipitation. Int J Pharm 243:83–91CrossRefGoogle Scholar
  32. 32.
    Gallo GG, Radaelli P (1976) Rifampin. In: Analytical Profiles of Drug Substances, vol 5. 467–513.
  33. 33.
    Vicosa A, Letourneau J-J, Espitalier F, Re MI (2 012) An innovative antisolvent precipitation process as a promising technique to prepare ultrafine rifampicin particles. J Cryst Growth 342:80–87Google Scholar

Copyright information

© Akadémiai Kiadó 2018

Authors and Affiliations

  1. 1.College of Biotechnology and Pharmaceutical EngineeringNanjing Tech UniversityNanjingChina
  2. 2.State Key Laboratory of Materials-Oriented Chemical EngineeringNanjing Tech UniversityNanjingChina

Personalised recommendations