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Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

Zhiqun Yu^†, Hei Dong^†, Xiaoxuan Xie^†, Jiming Liu^‡, and Weike Su^*^†^‡

^† National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China

^‡ Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00238

Publication Date (Web): November 17, 2016

*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00238

Abstract

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

//////////////chlorosulfonylation, continuous-flow, diazotization, parallel side reaction

Abstract Image

Continuous flow Doebner–Miller synthesis of different quinaldines from respective anilines is demonstrated using sulfuric acid as a homogeneous catalyst. The extent of reaction was monitored for various parameters, namely, temperature, residence time, mole ratio of sulfuric acid to substrate, mole ratio of crotonaldehyde to substrate, and so forth. Continuous stirred reactors in series were used as a preferred configuration for this rection that generates byproduct in the form of sticky solid material. The approach has been extended for six different anilines, and the results are compared with batch reactions. Continuous stirred reactors in series with distributed dosing of crotonaldehyde facilitated a continuous flow reaction with lower byproduct formation, increased yields, and continuous workup and is a scalable approach.

Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

Maruti B. Yadav^†, Sourabh Kulkarni^†, Ramesh A. Joshi^‡, and Amol A. Kulkarni^*^†

^† Chem. Eng. & Process Dev. Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India

^‡ Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00179

Publication Date (Web): August 22, 2016

*E-mail: aa.kulkarni@ncl.res.in. Fax: +91-20-25902621.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00179

Mr. Maruti Yadav

Project Assistant

M.Sc. Organic Chemistry, Pune University, 2013

Email: yadavmb.rajhira@gmail.com

Process Development of API production in continuous flow

Dr. Amol A. Kulkarni

Dr. Amol A. Kulkarni is a Scientist in the Chemical Engineering Division at the National Chemical Laboratory. He did his B. Chem. Eng. (1998), M. Chem. Eng (2000) and Ph.D. in chemical engineering (2003) all from the University Dept. of Chem. Technology (UDCT, Mumbai). In 2004 he worked at the Max Planck Institute-Magdeburg (Germany) as a Alexander von Humboldt Research Fellow. At NCL he is driving a research program on the design of microreactors and exploring their applications for continuous syntheses including of nanoparticles. He has been awarded with the Max-Planck-Visiting Fellowship from the Max-Planck-Society, Munich for 2008-2011. His research areas include: (i) design and applications of microreactors, (ii) design of multiphase reactors, (iii) experimental and computational fluid dynamics, and (iv) nonlinear dynamics of coupled systems. He is an active member of Initiative for Research and Innovation in Science (IRIS) supported by Intel’s Education Initiative to organize National Science Fair and popularize science in India.

Research areas

Multiphase reactors and Microreactors
Process Development and Scale-up
Process Intensification & MAGIC Processes
Industrial Flow Processes

Contact

Dr. Amol A. Kulkarni
Scientist
Office: 529, PP-1 Building, CEPD
National Chemical Laboratory
Dr. Homi Bhabha Road
Pune 411008, India
Phone +91 20 2590 2153
Fax +91 20 2590 2621
E-mail aa.kulkarni@ncl.res.in

///////////Continuous Flow, Doebner–Miller Reaction, Isolation, Continuous Stirred Tank Reactors, chemical engeineering, process, Amol A. Kulkarni, ncl, pune

Improving chemical synthesis using flow reactors.

Expert Opin Drug Discov

Expert Opin Drug Discov 2007 Nov;2(11):1487-503

Charlotte Wiles, Paul Watts

Charlotte

Prof Paul Watts

http://www.pubfacts.com/fulltext_frame.php?PMID=23484600&title=Improving%20chemical%20synthesis%20using%20flow%20reactors.

Owing to the competitive nature of the pharmaceutical industry, researchers involved in lead compound generation are under continued pressure to identify and develop promising programmes of research in order to secure intellectual property.

The potential of a compound for therapeutic development depends not only on structural complexity, but also on the identification of synthetic strategies that will enable the compound to be prepared on the desired scale.

One approach that is of present interest to the pharmaceutical industry is the use of continuous flow reactors, with the flexible nature of the technology being particularly attractive as it bridges the changes in scale required between the initial identification of a target compound and its subsequent production.

Based on these factors, a significant programme of research is presently underway into the development of flow reactors as tools for the synthetic chemist, with the transfer of many classes of reaction successfully reported to date.

This article focuses on the application of continuous flow methodology to drug discovery and the subsequent production of pharmaceuticals.