Continuous preparation for rifampicin

Abstract

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.

This is a preview of subscription content, access via your institution.

Scheme 1
Scheme 2
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

References

  1. 1.

    Maggi CRPN, Ballotta R, Senst P (1966) Rifampicin: a new orally active rifamycin. Chemotherapia 11:8

    Google Scholar 

  2. 2.

    Anonymous (1973) Analytical profiles of drug substances. Academic Press, New York and London

    Google Scholar 

  3. 3.

    E. A. Anacleto Gianantonio, U. S. P. Office, Ed. (United States, 1970), vol. US 3542762

  4. 4.

    Bruzzese T (Holco investment Inc USA, 1979)

  5. 5.

    Leonardo Marsili CP, U. S. P. Office, Ed. (Current: Gruppo Lepetit SpA ( original: ARCHIFAR IND CHIM TRENTINO), Italy, 1975), vol. US3925366

  6. 6.

    Leonardo Marsili CP, U. S. P. Office, Ed. (Archifar Industrie Chimiche del Trentina S.p.A., Italy, 1976), vol. 3963705

  7. 7.

    Burke WJ, Murdock KC, Ec G (1954) Condensation of hydroxyaromatic compounds with formaldehyde and primary aromatic amines. J. Am. Chem. Soc. 76:1677–1679

    CAS  Article  Google Scholar 

  8. 8.

    Burke WJ, Kolbezen MJ, Stephens CW (1952) Condensation of naphthols with formaldehyde and primary amines1. J. Am. Chem. Soc. 74:3601–3605

    CAS  Article  Google 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. 72:4691–4694

    CAS  Article  Google 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. 71:609–612

    CAS  Article  Google 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, 7–13

  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, 20–21

  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, China

  14. 14.

    Judit Némethné-Sóvágó MB (2014) Microreactors: a new concept for chemical synthesis and technological feasibility. Mater Sci Eng 39:89–101

    Google Scholar 

  15. 15.

    Makarshin LL, Pai ZP, Parmon VN (2016) Microchannel systems for fine organic synthesis. Russ. Chem Rev 85:139–155

    CAS  Article  Google Scholar 

  16. 16.

    Wang K, Li L, Xie P, Luo G (2017) Liquid-liquid microflow reaction engineering. React Chem Eng 2:611–627

    CAS  Article  Google 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. 285–305

  18. 18.

    Tanimu A, Jaenicke S, Alhooshani K (2017) Heterogeneous catalysis in continuous flow microreactors: a review of methods and applications. Chem. Eng. J. 327:792–821

    CAS  Article  Google 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 29:107–147

    CAS  Article  Google 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 16:180–196

    CAS  Article  Google 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 15:714–730

    CAS  Article  Google 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 39:260–274

    CAS  Article  Google 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 13:520–542

    CAS  Article  Google 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 35:365–373

    Article  Google 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 5:82–86

    CAS  Article  Google 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 55:1373–1379

    CAS  Article  Google 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 3:1197–1204

    CAS  Article  Google 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 96:39–43

    CAS  Article  Google 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 17:1137–1141

    CAS  Article  Google Scholar 

  30. 30.

    Zhu YDKCaJ (2006) Effects of the medium pH values on rifamycin oxazino cyclic reaction. Chin J Antibiot 31(10):3

  31. 31.

    Reverchon E, De Marco I, Della Porta G (2002) Rifampicin microparticles production by supercritical antisolvent precipitation. Int J Pharm 243:83–91

    CAS  Article  Google Scholar 

  32. 32.

    Gallo GG, Radaelli P (1976) Rifampin. In: Analytical Profiles of Drug Substances, vol 5. 467–513. https://doi.org/10.1016/S0099-5428(88)60328-7

  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 342:80–87

Download references

Acknowledgements

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).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kai Guo.

Electronic supplementary material

ESM 1

(DOCX 313 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, X., Liu, Z., Qi, H. et al. Continuous preparation for rifampicin. J Flow Chem 8, 129–138 (2018). https://doi.org/10.1007/s41981-018-0017-2

Download citation

Keywords

  • Continuous flow synthesis
  • Coupling of reaction and separation
  • Rifampicin preparation