Mar 142017
Dimethylcarbamoylchlorid Strukturformel.svg
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PubChem 6598

Dimethylcarbamoyl Chloride


Mechanisms for the Formation of Dimethylcarbamoyl Chloride

Thionyl chloride is the most common reagent in process chemistry for the conversion of a carboxylic acid to an acid chloride. One of the primary factors is cost, since the reagent is inexpensive and represents one of the most cost-efficient ways of preparing acid chlorides. However, one disadvantage of thionyl chloride is the potential formation of dimethylcarbamoyl chloride, a known carcinogen in animal models, when used in combination with DMF as catalyst.

Dimethylcarbamoyl chloride is a reagent for transferring a dimethylcarbonyl group to alcoholic or phenolic hydroxyl groups forming dimethyl carbamates, usually having pharmacological or pesticidal activities. Because of its high toxicity and its carcinogenic properties shown in animal experiments and presumably also in humans,[1] dimethylcarbamoyl chloride can only be used under stringent safety precautions.

Production and occurrence

The production of dimethylcarbamoyl chloride from phosgene and dimethylamine (DMA) was reported as early as 1879 (reported as “Dimethylharnstoffchlorid” – dimethylurea chloride).[2]

Synthese von Dimethylcarbamoylchlorid (DMCC) mit Dimethylamin

Dimethylcarbamoyl chloride can be produced in high yields (90%) at 275 °C by reacting phosgene with gaseous dimethylamine in a flow reactor.[3] To suppress the formation of ureas excessive phosgene is used (in a 3:1 ratio).

The reaction can also be carried out at the laboratory scale with diphosgene or triphosgene and a aqueous dimethylamine solution in the two-phase system benzene+xylene/water in a stirred reactor with sodium hydroxide as an acid scavenger. However, considerably lower yields (56%) are achieved due to the hydrolysis sensitivity of dimethylcarbamoyl chloride .[4]

Dimethylcarbamoyl chloride is also formed (together with methyl chloride) when reacting phosgene with trimethylamine.[5]

Synthese von Dimethylcarbamoylchlorid (DMCC) mit Trimethylamin

A more recent process is based on dimethylamine chloride, which is converted practically quantitatively to dimethylcarbamoyl chloride on a palladium catalyst under pressure with carbon monoxide at room temperature.[6]

Synthese von Dimethylcarbamoylchlorid (DMCC) aus Chloramin

Dicarbamoyl chloride can also be formed in small amounts (0-20 ppm) from dimethylformamide (DMF) in the Vilsmeier-Haack reaction[7] or when DMF is used as a catalyst in the reaction of carboxylic acids with thionyl chloride to the corresponding carboxylic acid chlorides.[8]

Synthese von Dimethylcarbamoylchlorid (DMCC) mit Dimethylformamid (DMF)

The tendency towards dicarbamoyl chloride formation depends on the chlorination reagent (thionyl chloride> oxalyl chloride> phosphorus oxychloride) and is higher in the presence of a base. However, dicarbamoyl chloride hydrolyses very quickly to dimethylamine, hydrochloric acid and carbon dioxide (with a half-life of about 6 minutes at 0 °C) so that less than 3 ppm of dicarbamoyl chloride are found in the Vilsmeier product after aqueous work-up.[9]


Dimethylcarbamoyl chloride is a clear, colorless, corrosive and flammable liquid with a pungent odor and a tear-penetrating effect, which decomposes rapidly in water.[10]Because of its unpleasant, toxic, mutagenic and carcinogenic properties[11][12] it has to be used under extreme precautions.

Dimethylcarbamoyl chloride behaves like an acid chloride whose chlorine atom can be exchanged for other nucleophiles. Therefore, it reacts with alcohols, phenols and oximes to the corresponding N, N-dimethylcarbamates, with thiols to thiolourethanes, with amines and hydroxylamine to substituted ureas, and with imidazoles and triazoles to carbamoylazoles.[13]

Reaktionen von Dimethylcarbamoylchlorid (DMCC) mit Nukleophilen

Dimethylcarbamoyl chloride is less reactive and less selective to substrates with multiple nucleophilic centers than conventional acid chlorides.

Unsaturated conjugated aldehydes such as (2E)-butenal react with dimethylcarbamoyl chloride forming dienyl carbamates, which can be used as dienes in Diels-Alder reactions.[14]

Synthese von Dienylcarbamaten mit Dimethylcarbamoylchlorid (DMCC)

Alkali metal carboxylates react with dimethylcarbamoyl chloride forming the corresponding dimethylamides. Dimethylcarbamoyl chloride reacts with anhydrous sodium carbonate[15] or with excess dimethylamine to tetramethylurea.[16]

The reaction of dimethylcarbamoyl chloride with DMF forms tetramethylformamidinium[17] chloride which is a major intermediate in the preparation of tris(dimethylamino)methane, a reagent for the introduction of enamine functions in conjunction with activated methylene groups[18] and the preparation of amidines.[19]

Synthese von Tris(dimethylamino)methan mit Diemthylcarbamoylchlorid (DMCC)

Dimethylcarbamoyl chloride is a starting material for the insecticide class of the dimethyl carbamates[20] which act as inhibitors of acetylcholinesterase, including dimetilane,[21]and the related compounds isolane, pirimicarb and triazamate.

Synthesis of Dimetilan mit Dimethylcarbamoylchlorid

The quaternary ammonium compounds neostigmine[22] finds pharmaceutical applications as acetylcholinesterase inhibitors. It is obtained from 3-dimethylaminophenol and dimethylcarbamoyl chloride and subsequent quaternization with methyl bromide or dimethyl sulfate[23]

Synthese von Neostigmin mit Dimethylcarbamoylchlorid

and pyridostigmine, which is obtainable from 3-hydroxypyridine and dimethylcarbamoyl chloride and subsequent reaction with methyl bromide.[24]

Synthese von Pyridostigmin mit dimethylcarbamoylchlorid

Dimethylcarbamoyl chloride is also used in the synthesis of the benzodiazepine camazepam.[25]

Synthese von Camazepam mit Dimethylcarbamoylchlorid

Image result for Dimethylcarbamoyl Chloride

13c NMR




  1. Jump up^ R.P. Pohanish (2011) (in German), Sittig’s Handbook of Toxic and Hazardous Chemicals and Carcinogens, 6th Edition, Amsterdam: Elsevier, pp. 1045–1047, ISBN 978-1437778694
  2. Jump up^ W. Michler; C. Escherich (1879), “Ueber mehrfach substituirte Harnstoffe” (in German), Ber. Dtsch. Chem. Ges. 12 (1): pp. 1162–1164, doi:10.1002/cber.187901201303
  3. Jump up^ R.J. Slocombe; E.A. Hardy; J.H. Saunders; R.L. Jenkins (1950), “Phosgene derivatives. The preparation of isocyanates, carbamyl chlorides and cyanuric acid” (in German), J. Am. Chem. Soc. 72 (5): pp. 1888–1891, doi:10.1002/ja01161a009
  4. Jump up^ G. Karimipour; S. Kowkabi; A. Naghiha (2015), “New aminoporphyrins bearing urea derivative substituents: synthesis, characterization, antibacterial and antifungal activity” (in German), Braz. Arch. Biol. Technol. 58 (3), doi:10.1590/S1516-891320500024
  5. Jump up^ H. Babad; A.G. Zeiler (1973), “Chemistry of Phosgene” (in German), Chem. Rev. 73 (1): pp. 75–91, doi:10.1021/cr60281a005
  6. Jump up^ T. Saegusa; T. Tsuda; Y. Isegawa (1971), “Carbamoyl chloride formation from chloramine and carbon monoxide” (in German), J. Org. Chem. 36 (6): pp. 858–860, doi:10.1021/jo00805a033
  7. Jump up^ M. Stare; K. Laniewski; A. Westermark; M. Sjögren; W. Tian (2009), “Investigation on the formation and hydrolysis of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions using /GC/MS as the analytical detection method” (in German), Org. Process Res. Dev. 13 (5): pp. 857–862, doi:10.1021/op900018f
  8. Jump up^ D. Levin (1997), “Potential toxicological concerns associated with carboxylic acid chlorination and other reactions” (in German), Org. Process Res. Dev. 1 (2): pp. 182, doi:10.1021/op970206t
  9. Jump up^ A. Queen (1967), “Kinetics of the hydrolysis of acyl chlorides in pure water” (in German), Canad. J. Chem. 45 (14): pp. 1619–1629, doi:10.1139/v67-264
  10. Jump up^ C.B. Kreutzberger; R.A. Olofson (2001), “Dimethylcarbamoyl Chloride” (in German), e-EROS Encyclopedia of Reagents for Organic Synthesis, doi:10.1002/047084289X.rd319
  11. Jump up^ P. Jäger; C.N. Rentzea; H. Kieczka (2014) (in German), Carbamates and Carbamoyl Chloride, in Ullmann’s Fine Chemicals, Weinheim: Wiley-VCH, pp. 57–58, ISBN 978-3-527-33477-3
  12. Jump up^ “Dimethylcarbamoyl Chloride, CAS No. 79-44-7” (PDF). Report on Carcinogens, Thirteenth Edition (in German). National Toxicology Program, Department of Health and Human Services. Retrieved 2016-09-25.
  13. Jump up^ C.B. Kreutzberger, R.A. Olofson (2007-02-01). “Dimethylcarbamoyl Chloride” (in German). John Wiley&Sons, Ltd. Retrieved 2016-09-27.
  14. Jump up^ P.F. De Cusati; R.A. Olofson (1990), “A simple synthesis of 1-(1,3-butadienyl)carbonates and carbamates” (in German), Tetrahedron Lett. 31 (10): pp. 1405–1408, doi:10.1016/S0040-4039(00)88817-6
  15. Jump up^ J.K. Lawson Jr.; J.A.T. Croom (1963), “Dimethylamides from alkali carboxylates and dimethylcarbamoyl chloride” (in German), J. Org. Chem. 28 (1): pp. 232–235, doi:10.1021/jo1036a513
  16. Jump up^ US 3597478, M.L. Weakly, “Preparation of tetramethylurea”
  17. Jump up^ Z. Arnold (1959), “The preparation of tetramethylformamidinium salts and their vinylogues” (in German), Coll. Czech. Chem. Commun. 24: pp. 760–765, doi:10.1135/cccc19590760
  18. Jump up^ H. Meerwein; W. Florian; N. Schön; G. Stopp (1961), “Über Säureamidacetale, Harnstoffacetale und Lactamacetale” (in German), Justus Liebigs Ann. Chem. 641 (1): pp. 1–39, doi:10.1002/jlac.19616410102
  19. Jump up^ H. Bredereck; F. Effenberger; Th. Brendle (1966), “Synthese und Reaktionen von Trisdimethylaminomethan” (in German), Angew. Chem. 78 (2): pp. 147–148, doi:10.1002/ange.19660780212
  20. Jump up^ “Compendium of Pesticide Common Names” (in German). Alan Wood. Retrieved 2016-09-27.
  21. Jump up^ US 3452043, T. Grauer, H. Urwyler, “Production of 1-N,N-dimethylcarbamoyl-5-methyl-3-N,N-dimethyl-carbamoyl-oxy-pyrazole”
  22. Jump up^ J.A. Aeschlimann; M. Reinert (1931), “Pharmacological action of some analogues of physostigmine” (in German), J. Pharmacol. Exp. Ther. 43 (3): pp. 413–444
  23. Jump up^ US 1905990, J.A. Aeschlimann, “Disubstituted carbamic acid esters of phenols containing a basic constituent”
  24. Jump up^ US 2572579, “Disubstituted carbamic acid esters of 3-hydroxy-1-alkyl-pyridinium salts”
  25. Jump up^ DOS 2448015, “Verfahren zur Herstellung des 3-N,N-Dimethylcarbamoyl-oxy-1-methyl-5-phenyl-7-chlor-1,3-dihydro-2H-1,4-benzodiazepin-2-on”



A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

 PROCESS, spectroscopy, SYNTHESIS  Comments Off on A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines
Jan 062017

Graphical abstract: A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines


We have reported herein a catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles by which a series of five-ring-fused tetrahydroisoquinolines featuring an indoline scaffold were obtained as single diastereomers in moderate to high yields without any additives under mild conditions. Moreover, the current method provides a novel and convenient approach for the efficient incorporation of two biologically important scaffolds (tetrahydroisoquinoline and indoline).!divAbstract

A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

Xihong Liu,a   Dongxu Yang,a   Kezhou Wang,a  Jinlong Zhanga and   Rui Wang*ab  
*Corresponding authors
aSchool of Life Sciences, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, P. R. China
bState Key Laboratory of Chiroscience, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, P. R. China
Green Chem., 2017,19, 82-87

DOI: 10.1039/C6GC02517J


 ethyl 13b-nitro-8-tosyl-8,8a,13b,13c-tetrahydro-5H-indolo[2′,3′:3,4]pyrazolo[5,1- a]isoquinoline-9(6H)-carboxylate: White solid, m.p. 153 – 154 oC; 94% yield;
1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.30 – 7.13 (m, 5H), 7.1 (s, 1H), 7.05 – 6.94 (m, 1H), 6.94 – 6.87 (m, 1H), 6.59 (t, J = 7.6 Hz, 3H), 6.28 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.80 – 2.58 (m, 2H), 2.33 (s, 3H), 2.31 – 2.11 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 152.1, 144.6, 142.6, 134.0, 132.1, 129.3, 129.0, 128.7, 128.3, 127.5, 127.3, 126.2, 122.8, 121.1, 115.5, 104.5, 84.9, 70.7, 62.8, 48.5, 29.1, 21. 6, 14.3 ppm;
HRMS (ESI): C27H26N4NaO6S [M + Na]+ calcd: 557.1465, found: 557.1476.

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

/////////// catalyst-free,  1,3-dipolar cycloaddition, C,N-cyclic azomethine imines,  3-nitroindoles,  five-ring-fused tetrahydroisoquinolines

Towards automation of chemical process route selection based on data mining

 PROCESS  Comments Off on Towards automation of chemical process route selection based on data mining
Jan 062017

Graphical abstract: Towards automation of chemical process route selection based on data mining

A methodology for chemical routes development and evaluation on the basis of data-mining is presented. A section of the Reaxys database was converted into a network, which was used to plan hypothetical synthesis routes to convert a bio-waste feedstock, limonene, to a bulk intermediate, benzoic acid. The route evaluation considered process conditions and used multiple indicators, including exergy, E-factor, solvent score, reaction reliability and route redox efficiency, in a multi-criteria environmental sustainability evaluation. The proposed methodology is the first route evaluation based on data mining, explicitly using reaction conditions, and is amenable to full automation.


In the field of process and synthetic chemistry ‘clean synthesis’ has become one of the standard criteria for good, commercially viable synthesis routes. As a result synthetic and process chemists must be equipped with adequate methodologies for quantification of ‘cleanness’ or ‘greenness’ of alternative routes at the early phases of the development cycle. These new criteria, and the traditional criteria of cost, security of supply, health and safety (H&S), and risk, provide a balanced picture of sustainability of a future technology. Thus, there are two separate aspects to process chemistry: developing the chemistry and the process, and evaluating the overall process, which must occur in parallel. Evaluation of the proposed routes requires data. As data science rapidly evolves, chemistry will inevitably use more of the new tools of data mining and data analysis to automate the routine tasks, such as evaluation of process metrics. In this paper we show some initial results in automation of process evaluation based on deep data mining of process chemistry and multi-criteria decision making.

The evaluation of greenness is a mature field, with a large number of published and standardised approaches, of which many are adopted by industry. 1 However, all published methods are highly case-specific and rather labour-intensive. In the field of synthetic routes development one of the most exciting new areas is the potential for automation of synthesis planning using data mining.2 What has never been attempted before is to automate route generation and evaluation in a coherent methodology, which would aid process development at the early, data-lean, stages. For this we show how to automatically generate process options using a network representation of a section of Reaxys database,3 followed by their screening using multi-criteria decision making, see Fig. 1. As the methods mature and become commercially available, such integration and automation will produce significant savings of time, and would deliver a far more detailed view of the competing synthesis route options than is generally possible at the early stages of design.

To date, obtaining the data, assembling the network and finding potential synthesis routes can already be carried out in a fully automated fashion. Due to issues around data availability the connection to the analysis of the routes still has to be initiated manually, involving a data curation step. The subsequent analysis and multi-criteria decision making have been largely automated in this study. To our knowledge this is the first example of the analysis of synthesis routes generated from the network representation of Reaxys obtained through datamining, using reaction conditions and process data.

image file: c6gc02482c-f2.tif

Fig. 2 A section of a network of organic chemistry. Dots are species and arrows represent reactions.
  1. D. J. C. Constable, C. Jimenez-Gonzalez and A. Lapkin, in Green Chemistry Metrics, John Wiley & Sons, Ltd, Chichester, UK, 2009, pp. 228–247 
  2. S. Szymkuć, E. P. Gajewska, T. Klucznik, K. Molga, P. Dittwald, M. Startek, M. Bajczyk and B. A. Grzybowski, Angew. Chem., Int. Ed., 2016, 55, 5904–5937 
  3. Reed Elsevier Properties SA, Login – Reaxys Login Page [Internet], 2014 [accessed 2014 Jun 8]. Available from: Reaxys is a trademark, copyright owned by Relex Intellectual properties SA and used under licence.

Towards automation of chemical process route selection based on data mining

*Corresponding authors
aDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK
Green Chem., 2017,19, 140-152

DOI: 10.1039/C6GC02482C,!divAbstract

Professor Alexei Lapkin, FRSC

Professor Alexei Lapkin FRSC

Professor of Sustainable Reaction Engineering

Fellow of Wolfson College

Catalytic Reaction Engineering

Sustainable Chemical Technologies

Office Phone: 330141

University of Cambridge
Image result for Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK


MChem in Biochemistry, Novosibirsk State University, 1994

PhD in Chemical Engineering, University of Bath, 2000

Boreskov Institute of Catalysis, Novosibirsk, Russia (1994-1997)

University of Bath, Department of Chemical Engineering, Research Officer (1997-2000)

University of Bath, Department of Chemical Engineering, Lecturer-SL-Reader (2000-2009)

University of Warwick, School of Engineering, Professor of Engineering (2009-2013)

Research Interests

Reaction Engineering group

Our group is developing cleaner manufacturing processes within chemical and chemistry using industries. We are mainly focusing on liquid- and multi-phase catalytic and biochemical processes. Within the group we have pursued projects on developing functional materials for catalysts, adsorbents and reactors, design of multi-functional intensive reactors, modelling of reaction kinetics and integrated processes, linking reaction kinetics with computational fluid dynamics (CFD) and linking process modelling with life cycle assessment (LCA), integration of reactions and separation.

Public funding:

The group is currently involved in an EU project ‘RECOBA’ (, in which our group collaborates with Materials and Electronic Engineering at Cambridge to work on innovative measurement techniques for monitoring processes under reaction conditions.

We are involved in the EPSRC project on developing novel routes to platform and functional molecules from waste terpenes, led by University of Bath.

We are involved in “Dial a Molecule 2” network funded by EPSRC.


  • Reaction Engineering
  • flow
  • sustainability
  • heterogeneous catalysis
  • catalysis

Key Publications

J. Zakrzhewski, A.P. Smalley, M. Kabeshov, A. Lapkin, M. Gaunt, Continuous flow synthesis and derivatization of aziridines via palladium-catalyzed C(sp3)-H activation, Angew. Chem. Int. Ed., 55 (2016) 8878-8883.

P. Yaseneva, P. Hodgson, J. Zakrzewski, S. Falss, R.E. Meadows, A.A. Lapkin, Continuous flow Buchwald-Hartwig amination of a pharmaceutical intermediate, React. Chem. Eng., 1 (2016) 229-238.

P. Yaseneva, D. Plaza, X. Fan, K. Loponov, A. Lapkin, Synthesis of the antimalarial API artemether in a flow reactor, Catal. Today, 239 (2015) 90-96.

N. Peremezhney, E. Hines, A. Lapkin, C. Connaughton, Combining Gaussian processes, mutual information and a generic algorithm for multi-targeted optimisation of expensive-to-evaluate functions, Engineering Optimisation, 46 (2014) 1593-1607.

P. Yaseneva, C.F. Marti, E. Palomares, X. Fan, T. Morgan,P.S. Perez, M. Ronning, F. Huang,T. Yuranova, L. Kiwi-Minsker, S. Derrouiche, A.A. Lapkin, Efficient reduction of bromates using carbon nanofibre supported catalysts: experimental and a comparative life cycle assessment study, Chem. Eng. J., 248 (2014) 230-241

K.N. Loponov, J. Lopes, M. Barlog, E.V. Astrova, A.V. Malkov, A.A. Lapkin, Optimization of a Scalable Photochemical Reactor for Reactions with Singlet Oxygen, Org.Process Res.Dev., 18 (2014) 1443-1454.

X. Fan, V. Sans, P. Yaseneva, D. Plaza, J.M.J. Williams, A.A. Lapkin, Facile Stoichiometric Reductions in Flow: an Example of Artemisinin, Org.Process Res.Dev., 16 (2012) 1039-1042.

M.V. Sotenko, M. Rebros, V.S. Sans, K.N. Loponov, M.G. Davidson, G. Stephens, A.A. Lapkin, Tandem transformation of glycerol to esters, J. Biotechnol., 162 (2012) 390-397.

A.A. Lapkin, A. Voutchkova, P. Anastas, A conceptual framework for description of complexity in intensive chemical processes, Chem. Eng. Processing. Process intensification, 50 (2011) 1027-1034.

Lapkin, A., Peters, M., Greiner, L., Chemat, S., Leonhard, K., Liauw, M. A. and Leitner, W., Screening of new solvents for artemisinin extraction process using ab-initio methodology, Green Chem., 12 (2010) 241-251.

Lapkin, A. A. and Plucinski, P. K., Engineering factors for efficient flow processes in chemical industries, in Chemical reactions and processes under flow conditions, pp. 1- 43, Eds: Luis, S. V. and Garcia-Verdugo, E., Royal Society of Chemistry, Cambridge, 2010.

Iwan, A., Stephenson, H., Ketchie, W. C. and Lapkin, A. A., High temperature sequestration of CO2 using lithium zirconates, Chem. Eng. J., 146 (2009) 249-258.

Constable, D. J. C., Jimenez-Gonzalez, C. and Lapkin A., ‘Process metrics’, in Green chemistry metrics: measuring and monitoring sustainable processes, pp.  228- 247, Eds.: Lapkin, A. and Constable, D. J. C., Wiley-Blackwell, Chichester, 2008.

L.Torrente-Murciano, A.Lapkin, D.V. Bavykin, F.C. Walsh, K. Wilson, Highly selective Pd/titanate nanotubes catalysts for the double bond migration reaction, J. Catal., 245 (2007) 270-276.

A. Lapkin, P. Plucinski, Comparative assessment of technologies for extraction of artemisinin, J. Natural Prod., 69 (2006) 1653-1664.

D.V. Bavykin, A.A. Lapkin, S.T. Kolaczkowski, P.K. Plucinski, Selective oxidation of alcohols in a continuous multifunctional reactor: ruthenium oxide catalysed oxidation of benzyl alcohol, Applied Catal. A: General, 288 (2005) 165-174.

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////////automation, chemical process,  route selection, data mining


Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

 PROCESS, SYNTHESIS, Uncategorized  Comments Off on Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction
Oct 202016


Abstract Image

The design, development, and scale up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at milligram scale through the development process leading to full-scale production in manufacturing under GMP conditions. Key aspects in this process include a description of drivers for developing a continuous process over existing well-defined batch approaches, manufacturing setup, and approaches toward key quality and regulatory questions such as batch definition, the use of process analytics, start up and shutdown waste, “in control” versus “at steady state”, lot genealogy and deviation boundaries, fluctuations, and diverting. The fully developed continuous reaction operated for 24 days during a primary stability campaign and produced over 2 MT of the penultimate intermediate in 95% yield after batch workup, crystallization, and isolation.


Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland
D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00148
Publication Date (Web): October 19, 2016
Copyright © 2016 American Chemical Society
*E-mail (Scott A. May):, *E-mail: (Martin D. Johnson):, *E-mail: (Declan D. Hurley)

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.



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

 PROCESS, Uncategorized  Comments Off on Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors
Aug 312016

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

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
Copyright © 2016 American Chemical Society
*E-mail: Fax: +91-20-25902621.
Image result for Maruti B. Yadav ncl
Mr. Maruti Yadav
Project Assistant
M.Sc. Organic Chemistry, Pune University, 2013
Process Development of API production in continuous flow

Image result for amol kulkarni ncl
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


  • Dr. Amol A. Kulkarni
    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

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


Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages

 companies, INDIA, MANUFACTURING, new drugs, PRECLINICAL, PROCESS, regulatory  Comments Off on Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages
Jul 162016



Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability  to  design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………


Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or  by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands,  heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks.  They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;










See presentation below


Managing Director at Sreeni Labs Private Limited


Few Case Studies : Source SEEENI LABS


One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.


One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.


One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.


One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.


Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers.  We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.


One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO  for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide,  palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route  in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.


One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.  



The man behind Seeni labs is Dr.Sreenivasa  Reddy Mundla

Sreenivasa Reddy

Dr. Sreenivasa Reddy Mundla

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

  • IDA, Nacharam
    Hyderabad, 500076
    Telangana State, India






Dr. Sreenivasa Mundla Reddy

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000,  worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. 

In 2007  resigned to his  job and founded Sreeni Labs based in Hyderabad, Telangana, India  and started working with various global customers and solving various challenging synthesis problems. 
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale.

They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects


Founder & Managing Director

Sreeni Labs Private Limited

August 2007 – Present (8 years 11 months)

Sreeni Labs Profile

Sreeni Labs Profile

View On SlideShare

Principal Research Scientist

Eli Lilly and Company

March 2001 – August 2007 (6 years 6 months)

Senior Research Scientist

Procter & Gamble

July 1994 – February 2001 (6 years 8 months)


University of Hyderabad

Doctor of Philosophy (Ph.D.), 
1986 – 1992



Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

Read full-textSource

Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

Read at


Patents by Inventor Dr. Sreenivasa Reddy Mundla

  • Patent number: 7872020

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Grant

    Filed: June 29, 2006

    Date of Patent: January 18, 2011

    Assignee: Eli Lilly and Company

    Inventor: Sreenivasa Reddy Mundla

  • Publication number: 20100120854

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Application

    Filed: June 29, 2006

    Publication date: May 13, 2010


    Inventor: Sreenivasa Reddy Mundla

  • Patent number: 6066740

    Abstract: The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.

    Type: Grant

    Filed: November 25, 1997

    Date of Patent: May 23, 2000

    Assignee: The Procter & Gamble Company

    Inventors: Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth

TGF-β inhibitors

US 7872020 B2

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

Figure US07872020-20110118-C00002

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Figure US07872020-20110118-C00008


1H NMR (CDCl3): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16



Phase III


CAS No.700874-72-2




Accelerating Generic Approvals, see how you can accelerate your drug development programme

Accelerating Generic Approvals by Dr Anthony Crasto

KEYWORDS   Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India,  new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3,  API, drugs, medicines


Nickel-Catalyzed Decarbonylative Suzuki–Miyaura Coupling of Amides To Generate Biaryls

 PROCESS, spectroscopy, SYNTHESIS  Comments Off on Nickel-Catalyzed Decarbonylative Suzuki–Miyaura Coupling of Amides To Generate Biaryls
Jul 112016

Thumbnail image of graphical abstract

Shi et al. have reported a nickel-catalyzed decarbonylative Suzuki–Miyaura reaction which uses an N-aroylpiperidine-2,6-dione as the coupling partner for the boronic acid ( Angew. Chem., Int. Ed. 2016, 55, 6959−6963).
The method is attractive from the point of view of the stability of N-aroylpyrrolidine-2,5-diones toward storage and manipulation and the flexibility they add to the chemist’s toolbox, given their preparation from a different group of precursors to aryl halides or triflates.
Notably, the reaction uses an air-stable and inexpensive nickel catalyst, and the reactions tolerate the presence of water. While a standard reaction temperature of 150 °C is quoted, the use of temperatures as low as 80 °C also seem to be possible. Coupling efficiency is reported to be adversely affected when the aromatic rings of both of the coupling partners bear electron-donating substituents.
Ortho substituents on the aromatic rings seem to be beneficial as they facilitate decarbonylation as part of the cross-coupling. Oxidative addition into the N–C(aroyl) bond of the amide is proposed as initiating the catalytic cycle and is possible on account of a reduction in the resonance stabilization of the N-aroyl functionality versus a conventional aromatic amide.

Suzuki–Miyaura Coupling

Synthesis of Biaryls through Nickel-Catalyzed Suzuki–Miyaura Coupling of Amides by Carbon–Nitrogen Bond Cleavage (pages 6959–6963)Shicheng Shi, Guangrong Meng and Prof. Dr. Michal Szostak

Version of Record online: 21 APR 2016 | DOI: 10.1002/anie.201601914

Thumbnail image of graphical abstract

Breaking and making: The first nickel-catalyzed Suzuki–Miyaura coupling of amides for the synthesis of biaryl compounds through N−C amide bond cleavage is reported. The reaction tolerates a wide range of sensitive and electronically diverse substituents on both coupling partners.



1H NMR (500 MHz, CDCl3) δ 7.70 (s, 4 H), 7.61 (d, J = 7.3 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.42 (t, J = 7.3 Hz, 1 H).



13C NMR (125 MHz, CDCl3) δ 144.87, 139.92, 129.48 (q, J F = 32.5 Hz), 129.13, 128.32, 127.56, 127.42, 125.83 (q, J F = 3.8 Hz), 124.46 (q, J F = 270.0 Hz).



19F NMR (471 MHz, CDCl3) δ -62.39.

//////Nickel-Catalyzed,  Decarbonylative Suzuki–Miyaura Coupling,  Amides, Biaryls


Review, Continuous Processing

 PROCESS, spectroscopy, SYNTHESIS, Uncategorized  Comments Off on Review, Continuous Processing
Jun 272016

Continuous Processing


Continuous production is a flow production method used to manufacture, produce, or process materials without interruption. Continuous production is called a continuous process or a continuous flow process because the materials, either dry bulk or fluids that are being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production.

Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Some chemical plants can operate for more than one or two years without a shutdown. Blast furnaces can run four to ten years without stopping.[1]

Production workers in continuous production commonly work in rotating shifts.

Processes are operated continuously for practical as well as economic reasons. Most of these industries are very capital intensive and the management is therefore very concerned about lost operating time.

Shutting down and starting up many continuous processes typically results in off quality product that must be reprocessed or disposed of. Many tanks, vessels and pipes cannot be left full of materials because of unwanted chemical reactions, settling of suspended materials or crystallization or hardening of materials. Also, cycling temperatures and pressures from starting up and shutting down certain processes (line kilns, boilers, blast furnaces, pressure vessels, etc.) may cause metal fatigue or other wear from pressure or thermal cycling.

In the more complex operations there are sequential shut down and start up procedures that must be carefully followed in order to protect personnel and equipment. Typically a start up or shut down will take several hours.

Continuous processes use process control to automate and control operational variables such as flow rates, tank levels, pressures, temperatures and machine speeds.[2]

Semi-continuous processes

Many processes such as assembly lines and light manufacturing that can be easily shut down and restarted are today considered semi-continuous. These can be operated for one or two shifts if necessary.


The oldest continuous flow processes is the blast furnace for producing pig iron. The blast furnace is intermittently charged with ore, fuel and flux and intermittently tapped for molten pig iron and slag; however, the chemical reaction of reducing the iron and silicon and later oxidizing the silicon is continuous.

Semi-continuous processes, such as machine manufacturing of cigarettes, were called “continuous” when they appeared.

Many truly continuous processes of today were originally batch operations.

The Fourdrinier paper machine, patented in 1799, was one of the earliest of the industrial revolution era continuous manufacturing processes. It produced a continuous web of paper that was formed, pressed, dried and reeled up in a roll. Previously paper had been made in individual sheets.

Another early continuous processes was Oliver Evans‘es flour mill (ca. 1785), which was fully automated.

Early chemical production and oil refining was done in batches until process control was sufficiently developed to allow remote control and automation for continuous processing. Processes began to operate continuously during the 19th century. By the early 20th century continuous processes were common.


In addition to performing maintenance, shut downs are also when process modifications are performed. These include installing new equipment in the main process flow or tying-in or making provisions to tie-in sub-processes or equipment that can be installed while the process is operating.

Shut-downs of complicated processes may take weeks or months of planning. Typically a series of meetings takes place for co-ordination and planning. These typically involve the various departments such as maintenance, power, engineering, safety and operating units.

All work is done according to a carefully sequenced schedule that incorporates the various trades involved, such as pipe-fitters, millwrights, mechanics, laborers, etc., and the necessary equipment (cranes, mobile equipment, air compressors, welding machines, scaffolding, etc.) and all supplies (spare parts, steel, pipe, wiring, nuts and bolts) and provisions for power in case power will also be off as part of the outage. Often one or more outside contractors perform some of the work, especially if new equipment is installed.


Safety meetings are typically held before and during shutdowns. Other safety measures include providing adequate ventilation to hot areas or areas where oxygen may become depleted or toxic gases may be present and checking vessels and other enclosed areas for adequate levels of oxygen and insure absence of toxic or explosive gases. Any machines that are going to be worked on must be electrically disconnected, usually through the motor starter, so that it cannot operate. It is common practice to put a padlock on the motor starter, which can only be unlocked by the person or persons who is or are endangered by performing the work. Other disconnect means include removing couplings between the motor and the equipment or by using mechanical means to keep the equipment from moving. Valves on pipes connected to vessels that workers will enter are chained and locked closed, unless some other means is taken to insure that nothing will come through the pipes.

Continuous processor (equipment)

Continuous Production can be supplemented using a Continuous Processor. Continuous Processors are designed to mix viscous products on a continuous basis by utilizing a combination of mixing and conveying action. The Paddles within the mixing chamber (barrel) are mounted on two co-rotating shafts that are responsible for mixing the material. The barrels and paddles are contoured in such a way that the paddles create a self-wiping action between themselves minimizing buildup of product except for the normal operating clearances of the moving parts. Barrels may also be heated or cooled to optimize the mixing cycle. Unlike an extruder, the Continuous Processor void volume mixing area is consistent the entire length of the barrel ensuring better mixing and little to no pressure build up. The Continuous Processor works by metering powders, granules, liquids, etc. into the mixing chamber of the machine. Several variables allow the Continuous Processor to be versatile for a wide variety of mixing operations:[3]

  1. Barrel Temperature
  2. Agitator speed
  3. Fed rate, accuracy of feed
  4. Retention time (function of feed rate and volume of product within mixing chamber)

Continuous Processors are used in the following processes:

  • Compounding
  • Mixing
  • Kneading
  • Shearing
  • Crystallizing
  • Encapsulating

The Continuous Processor has an unlimited material mixing capabilities but, it has proven its ability to mix:

  • Plastics
  • Adhesives
  • Pigments
  • Composites
  • Candy
  • Gum
  • Paste
  • Toners
  • Peanut Butter
  • Waste Products




Abstract Image

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Org. Process Res. Dev., 2014, 18 (11), pp 1427–1433


Correia et al. have published a three-step flow synthesis of rac-Effavirenz. This short synthetic route begins with cryogenic trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO3)2 and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO3)2, Cu(OTf)2 was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date
1H NMR (400 MHz, CDCl3, ppm) δ9.45 (s, 1H), 7.49 (s, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.43-1.36 (m, 1H); 0.93-0.85 (m, 4H);
13C NMR (100 MHz, CDCl3, ppm) δ 149.2, 133.2, 131.7, 129.2, 127.8, 122.1 (q, JC-F = 286 Hz), 116.3, 115.1, 95.9, 79.6 (q, JC-F = 35 Hz), 66.1, 8.8, 0.6;
19F NMR (376 MHz, CDCl3, ppm) δ -80.98.
1 T. J. Connolly; A. W.-Y Chan; Z. Ding; M. R. Ghosh; X. Shi; J. Ren, E. Hansen; R. Farr; M. MacEwan; A. Alimardanov; et al, PCT Int. Appl. WO 2009012201 A2 20090122, 2009.
2 (a) Z. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, (Lonza Ltd), PCT Int. Appl. WO2012097510, 2012; (b) D. D. Christ; J. A. Markwalder; J. M. Fortunak; S. S. Ko; A. E. Mutlib; R. L. Parsons; M. Patel; S. P. Seitz, PCT Int. Appl. WO 9814436 A1 19980409, 1998 (c) C. A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517−3521.

A Concise Flow Synthesis of Efavirenz

  • DOI: 10.1002/anie.201411728



Wang et al. developed a flow process that uses metal catalyzed hydrogenation of NAB (2-nitro-2′-hydroxy-5′-methylazobenzene) to BTA (2-(2′-hydroxy-5′-methylphenyl)benzotriazole), a commonly used ultraviolet absorber. The major challenge in this process was to optimize the reduction of the diazo functionality over the nitro group and control formation of over reduction side products. The initial screen of metals adsorbed onto a γ-Al2O3 support indicated Pd to be superior to the other metals and also confirmed that catalyst preparation plays an important role in selectivity. To better understand the characteristics of the supported metal catalyst systems, the best performing were analyzed by TEM, XRD, H2-TPR, and N2 adsorption–desorption. Finally, solvents and bases were screened ultimately arriving at the optimized conditions using toluene, 2 equiv n-butylamine over 1% Pd/Al2O3, which provided 90% yield BTA in process with 98% conversion. The process can run over 200 h without a decrease in performance
( ACS Sustainable Chem. Eng. 2015, 3,1890−1896)
Abstract Image

The synthesis of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole from 2-nitro-2′-hydroxy-5′-methylazobenzene over Pd/γ-Al2O3 in a fixed-bed reactor was investigated. Pd/γ-Al2O3 catalysts were prepared by two methods and characterized by XRD, TEM, H2-TPR, and N2 adsorption–desorption. Employed in the above reaction, the palladium catalyst impregnated in hydrochloric acid exhibited much better catalytic performance than that impregnated in ammonia–water, which was possibly attributed to the better dispersion of palladium crystals on γ-Al2O3. This result demonstrated that the preparation process of the catalyst was very important. Furthermore, the reaction parameters were optimized. Under the optimized conditions (toluene, NAB/triethylamine molar ratio 1:2, 60 °C, 2.5 MPa hydrogen pressure, 0.23 h–1 liquid hourly space velocity), about 90% yield of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole was obtained. Finally, the time on stream performance of the catalyst was evaluated, and the reaction could proceed effectively over 200 h without deactivation of the catalyst.

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al2O3 by a Continuous Process

ACS Sustainable Chem. Eng., 2015, 3 (8), pp 1890–1896
DOI: 10.1021/acssuschemeng.5b00507
Publication Date (Web): July 06, 2015



Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

continuous flow processing of organometallic reagents

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.




Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

A versatile multi-step continuous flow synthesis for the preparation of substituted pyrazoles is presented.

The automated synthesis utilises a metal-free ascorbic acid mediated reduction of diazonium salts prepared from aniline starting materials followed by hydrolysis of the intermediate hydazide and cyclo-condensation with various 1,3-dicarbonyl equivalents to afford good yields of isolated functionalised pyrazole products.

The synthesis of the COX-2 selective NSAID was demonstrated using this approach.



Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient



RAFT RAFT (Reversible Addition Fragmentation chain Transfer), a type of controlled radical polymerization, was invented by CSIRO in 1998 but developed in partnership with DuPont over a long term collaboration. Conventional polymerisation is fast but gives a wide distribution of polymer chain lengths. (known as a high polydispersity index ). RAFT is more versatile than other living polymerization techniques, such as atom transfer radical polymerization (ATRP) or nitroxide-mediated polymerization (NMP), it not only leads to polymers with a low polydispersity index and a predetermined molecular weight, but it permits the creation of complex architectures, such as linear block copolymers, comblike, star, brush polymers and dendrimers. Monomers capable of polymerizing by RAFT include styrenes, acrylates, acrylamides, and many vinyl monomers. CSIRO is the owner of the RAFT patents and is actively commercialising the technology. There are 12 licences in force and CSIRO is pursuing interest in a number of fields including human health, agriculture, animal health and personal care. RAFT is the dominant polymerization technique for the creation of polymer-protein or polymer-drug conjugates, permitting (for example) the combination of a polymer exhibiting high solubility with a drug molecule with poor solubility.. Though RAFT can be carried out in batch, it also lends itself to continuous flow processing, as this processing method offers an easy and reproducible scale-up route of the oxygen sensitive RAFT process. The possibility to effectively exclude oxygen using continuous flow reactors in combination with inline degassing methods offers advantages over batch processing at scales beyond the laboratory environment. Challenges associated with the high viscosity of the polymer product solution can be controlled using pressuriseable continuous flow reactor systems.


Cyclohexaneperoxycarboxylic acid (6,  has been developed as a safe, inexpensive oxidant, with demonstrated utility in a Baeyer−Villiger rearrangement.34 Solutions of cyclohexanecarboxylic acid in hexane and 50% aqueous H2O2 were continuously added to 45% H2SO4 at 50−70 °C and slightly reduced pressure. The byproduct H2O was removed azeotropically, and the residence time in the reactor was 3 h. Processing was adjusted to maintain a concentration of 6 at 17−19%, below the detonable level, and the product was kept as a stable solution in hexane. These operations enhanced the safety margin in preparing 6.


Scheme .  Generation of cyclohexaneperoxycarboxylic acid


Abstract Image

The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4,d-erythronolactone at kilogram scale was used as an example. Fully continuousprocessing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Org. Process Res. Dev., 2012, 16 (5), pp 1003–1012



Abstract Image

Continuous Biocatalytic Processes

Org. Process Res. Dev., 2009, 13 (3), pp 607–616
Scheme . Biotransformation of sodium l-glutamate to γ-aminobutyric acid (GABA) by single-step α-decarboxylation with glutamate decarboxylase



  1.  American Iron and Steel Institute
  2.  Benett, Stuart (1986). A History of Control Engineering 1800-1930. Institution of Engineering and Technology. ISBN 978-0-86341-047-5.
  3.  Ziegler, Gregory R.; Aguilar, Carlos A. (2003). “Residence Time Distribution in a Co-rotating, Twin-screw Continuous Mixer by the Step Change Method”. Journal of Food Engineering(Elsevier) 59 (2-3): 1–7.

Sources and further reading

  • R H Perry, C H Chilton, C W Green (Ed), Perry’s Chemical Engineers’ Handbook (7th Ed), McGraw-Hill (1997), ISBN 978-0-07-049841-9
  • Major industries typically each have one or more trade magazines that constantly feature articles about plant operations, new equipment and processes and operating and maintenance tips. Trade magazines are one of the best ways to keep informed of state of the art developments.

PIERRE FABRE CDMO Supercritical Fluids – A supercritical CO2 GMP Unit for Pharmaceutical Applications.

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Pierre Fabre



Gaillac, france

Map of Gaillac France
Commune in France
Gaillac is a commune in the Tarn department in southern France. It had in 2013 a population of 14,334 inhabitants. Wikipedia


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