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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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New Website online! from C. Oliver Kappe, University of Graz

New Website online!

C. Oliver Kappe

Professor at University of Graz

Institute of Chemistry

Univ.-Prof. Mag. Dr.rer.nat.

+43 316 380-5352
+43 (0) 316 380 – 9840

Research in the Kappe lab focuses on flow chemistry, microreactor technology, process intensification and the continuous generation of active pharmaceutical ingredients (APIs). Check out our new webiste at:

Recent Hot Papers from the Kappe Lab

Web of Science Highly Cited and Hot Article

Continuous Flow Technology – A Tool for the Manufacturing of Active Pharmaceutical Ingredients
B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015 , 54, 6688-6729.
DOI: 10.1002/anie.201409318

Chemistry – A European Journal Hot Paper
Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals – A Fast and Scalable Protocol for Trifluoromethylation
J. L. Monteiro, P. F. Carneiro, P. Elsner, D. Roberge, P. G. M. Wuts, K. Kurjan, B. Gutmann, C. O. Kappe,
Chem. Eur. J. 2017 , 23, in press.
DOI: 10.1002/chem.201604579

Journal of Organic Chemistry Featured Article
A Lab-Scale Membrane Reactor for the Generation of Anhydrous Diazomethane
D. Dallinger, V. D. Pinho, B. Gutmann, C. O. Kappe, J. Org. Chem. 2016 , 81, 5814-5823.
DOI: 10.1021/acs.joc.6b01190

Active Pharmaceutical Ingredients (APIs) in Flow

Continuous flow processes form the basis of the petrochemical and bulk chemicals industry where strong competition, stringent environmental and safety regulations, and low profit margins drive the need for highly performing, cost effective, safe and atom efficient chemical operations. In contrast to the commodity chemical industry, however, the fine chemical industry primarily relies on its existing infrastructure of multipurpose batch or semi-batch reactors. Fine chemicals, such as drug substances and active pharmaceutical ingredients (APIs), are generally considerably more complex than commodity chemicals and usually require numerous, widely diverse reaction steps for their synthesis (typically 6 to 10 synthetic steps), and multiple rounds of quenching, separation and purification. These requirements, together with the comparatively low production volumes and often short life time of many of these materials, make versatile and reconfigurable multipurpose batch reactors the technology of choice for their preparation. However, the advantages of continuous flow processing are increasingly being appreciated also by the pharmaceutical industry and, thus, a growing number of scientists, from research chemists in academia to process chemists and chemical engineers in pharmaceutical companies, are now starting to employ continuous flow technologies on a more routine basis. Together with our industrial partners, the Kappe laboratories are involved in numerous flow API synthesis projects.


Key Publications

Review: Continuous-Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients
B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688-6729. DOI: 10.1002/anie.201409318 (Web of Science “Highly Cited Paper”).

Towards the Synthesis of Noroxymorphone via Aerobic Palladium-Catalyzed Continuous Flow N-Demethylation Strategies. B. Gutmann, P. Elsner, D. P. Cox, U. Weigl, D. M. Roberge, C. O. Kappe, ACS Sust. Chem. Eng. 2016, 4, in press. DOI: 10.1021/acssuschemeng.6b01371

Batch and Continuous Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines – A Concise Synthesis of Noroxymorphone
B. Gutmann, U. Weigl, D. P. Cox, C. O. Kappe, Chem. Eur. J. 2016, 22, 10393–10398. DOI:10.1002/chem.201601902 (selected as ”Hot Paper” by the Editors).

Selective Olefin Reduction in Thebaine Using Hydrazine Hydrate and O2 under Intensified Continuous Flow Conditions
B. Pieber, D. P. Cox, C. O. Kappe, Org. Process Res. Develop. 2016, 20, 376−385. DOI: 10.1021/acs.oprd.5b00370

Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles: Toward the Continuous Production of Daclatasvir
P. F. Carneiro, B. Gutmann, R. O. M. A. de  Souza, C. O. Kappe, ACS Sust. Chem. Eng. 2015, 3, 3445−3453. DOI: 10.1021/acssuschemeng.5b01191

Continuous Flow Reduction of Artemisinic Acid Utilizing Multi-Injection Strategies – Closing the Gap Towards a Fully Continuous Synthesis of Antimalarial Drugs
B. Pieber, T. Glasnov, C. O. Kappe, Chem. Eur. J. 2015, 21, 4368-4376. DOI: 10.1002/chem.201406439 (selected as “Hot Paper“ by the Editors, covered by Chemical & Engineering News).

Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions
B. Gutmann, P. Elsner, A. O’Kearney-McMullan, W. Goundry, D. M. Roberge, C. O. Kappe, Org. Process Res. Develop. 2015, 19, 1062-1067. DOI: 10.1021/acs.oprd.5b00217

Continuous Flow Synthesis of alpha-Haloketones – Essential Building Blocks of Antiretroviral Agents
V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A. de Souza, C. O. Kappe, J. Org. Chem. 2014, 79, 1555-1562. DOI: 10.1021/jo402849z (selected as “Featured Article” by the Editors).

Combined Batch and Continuous Flow Procedure to the Chemo-Enzymatic Synthesis of Biaryl Moiety of Odanacatib.
R. de Oliveira Lopes, A. S. de Miranda, B. Reichart, T. Glasnov, C. O. Kappe, R. C. Simon, W. Kroutil, L. S. M. Miranda, I. C. R.Leal, R. O. M. A. de Souza, J. Mol. Catal. B. 2014, 104, 101-107. DOI: 10.1016/j.molcatb.2014.03.017

On the Fischer Indole Synthesis of 7-Ethyltryptophol- Mechanistic and Process Intensification Studies under Continuous Flow Conditions.
B. Gutmann, M. Gottsponer, P. Elsner, D. Cantillo, D. M. Roberge, C. O. Kappe, Org. Process Res. Develop. 2013, 17, 294-302. DOI: 10.1021/op300363s

A Three Step Continuous Flow Synthesis of the Biaryl Unit of the HIV Protease Inhibitor Atazanavir.
L. Dalla-Vechia, B. Reichart, T. N. Glasnov, L. S. M. Miranda, C. O. Kappe, R. O. M. A. de Souza, Org. Biomol. Chem. 2013, 11, 6806-6813. DOI: 10.1039/c3ob41464g

A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones.
M. Viviano, T. N. Glasnov, B. Reichart, G. Tekautz, C. O. Kappe, Org. Process Res. Develop. 2011, 15, 858-870. DOI: 10.1021/op2001047

Image result for C. Oliver Kappe


////////////New Website,,  online,  C. Oliver Kappe, University of Graz, flow chemistry

Continuous Flow Stereoselective Synthesis of (S)-Warfarin


Continuous Flow Stereoselective Synthesis of (S)-Warfarin

The same catalytic packed-bed reactor was used for the preparation of (S)-warfarin 107 under continuous flow conditions (Scheme ).A solution of 4-OH-coumarin 104, benzalacetone105, and trifluoroacetic acid as a cocatalyst in dioxane was flowed into the reactor containing the polystyrene-supported 9-amino-epi-quinine 122. With a residence time of 5 h at 50 °C, we were able to isolate the product in up to 90% yield and up to 87% ee. Further studies are needed in order to optimize the reaction under continuous flow conditions; however, the proposed protocol already offers the possibility to extend catalyst’s lifetime, longer than in batch mode, further suggesting interesting future applications for the catalytic reactors.

The Pericàs group published the stereoselective Michael addition of ethyl nitroacetate to benzalacetone promoted by polystyrene-supported 9-amino-9-deoxy-epi-quinine 126 under continuous flow conditions. It should be pointed out that the polystyrene in our hands is a highly reticulated, insoluble polymer, while the polystyrene used by the Pericàs group is a swelling resin; a careful choice of the reaction solvent should be done, as this may affect the reaction course. The functionalized resin was packed into a Teflon tube between two plugs of glass wool. The reaction was run by pumping a solution of the two reagents and benzoic acid as a cocatalyst in CHCl3 (chosen after careful solvent screening) at 30 °C for 40 min residence time. Notably, 3.6 g (12.9 mmol) of the desired adducts were collected in 21 h of operation in roughly 1/1 dr and 97/98% ee.

Porta, R.; Benaglia, M.; Puglisi, A. Unpublished results.

Izquierdo, J.; Ayats, C.; Henseler, A. H.; Pericàs, M. A. Org. Biomol. Chem. 2015, 13, 4204, DOI: 10.1039/C5OB00325C


Image result for warfarin nmr

A polystyrene-supported 9-amino(9-deoxy)epi quinine derivative for continuous flow asymmetric Michael reactions

*Corresponding authors
aInstitute of Chemical Research of Catalonia (ICIQ), Avda. Països Catalans, 16, E-43007, Tarragona, Spain
bDepartament de Química Orgànica, Universitat de Barcelona (UB), E-08028, Barcelona, Spain
Fax: +34 977920244
Tel: +34 977920243
Org. Biomol. Chem., 2015,13, 4204-4209

DOI: 10.1039/C5OB00325C

A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions affording excellent levels of conversion and enantioselectivity using different nucleophiles and structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours without significant decrease in conversion and with improved enantioselectivity with respect to batch operation. The flow process has also been used for the sequential preparation of a small library of enantioenriched Michael adducts.

Graphical abstract: A polystyrene-supported 9-amino(9-deoxy)epi quinine derivative for continuous flow asymmetric Michael reactions
Image result for (S)-Warfarin


There are 3 types of Warfarin:

1. Racemic Warfarin

2. S-Warfarin

3. R-Warfarin

As there are different types different synthetic routes are required. Firstly, looking at the racemic Warfarin followed by the asymetric Warfarin (S- and R- Warfarin).

Racemic Warfarin Synthesis:

The usual synthetic route for racemic Warfarin involves a base/acid catalysed Michael condensation reaction of 4-hydroxycoumarin with benzalacetone. These reactants are either refluxed in water for approximately 4-8 hours or refluxed with pyridine which gives a saturated yield. The mechanism is shown below:

The yield when this reaction is reflux with water is 48%.

Asymetric Synthesis:

During recent years it has been found that one of the possible enantiomers usually has a pharmacological profile that is superior to the racemate. Hence pharmaceutical companies have been replacing exisiting racemic drugs with their pure enantiomeric form.

In the case of Warfarin it was found that S-Warfarin is the superior enantiomer being 6 times more active than R-Warfarin. There are 2 main methods to form a pure enantiomeric form of Warfarin.

1. Asymmetric hydrogenation: This was developed by DuPont Merk Pharmaceutical. It involves the a DuPHOS-Rh(I) catalysed hydrogenation of racemic Warfarin to give the desired enantiomer. Below is the reaction scheme for this synthesis:

This exclusive product is then used in the rest of the synthesis. First reacting it with NaOH to form the sodium salt of the product:

This, then, depending on the enantiomer that is desired, the sodium salt is hydrogenated using either (R,R)-Et-DuPHOS-Rh(I) or (S,S)-Et-DuPHOS-Rh(I) to give S-Warfarin and R-Warfarin respectively:

This route gives enantioselectivities of 82-86% e.e in methanol and 88% e.e in 3:2 isopropanol-methanol. Acidification and a single recrystallisation of the crude product gave R- and S- Warfarin in >98% e.e.

2. Hetero-Diels-Alder cycloaddition: This method was developed in 2001 and the key feature is that it does not use racemic Warfarin as a starting material. Instead it involves a hetero-Diels-Alder cycloaddition of a iso-propenyl ether to 4-hydroxycoumarin (via the use of dry dioxane and a Tietze Base with 5A Molecular sieves at a temperature of 80ºC):

Here S-Warfarin has been synthesised with an e.e of 95%.


General Data:

Chemical Names:
  • 4-hydroxy-3-(3-oxo-1-phenyl-butyl)-chromen-2-one
  • 3-(2-acetyl-1-phenylethyl)-4-hydroxycoumarin
  • (+ -)Warfarin


CAS Number:
Molecular Weight:
Optical Isomers: S-Warfarin and R-Warfarin
Melting Point /ºC :
Optical Rotation:
S-Warfarin : -25.5 ± 1º
R-Warfarin : +24.8 ± 1º

str1 str2



Tautomerization of warfarin substructures, whose combination generates 40 distinct tautomeric forms of warfarin

13 C NMR spectrum (A) and 1 H NMR spectrum (B) of warfarin. Arrows indicate peaks from the open-chain form of warfarin though the intensity is very low. See Figure 1 for numbering of the C atoms. H1(R) and H1(S) are connected to C15; H2 and H3 are connected to C13; and H4 is bonded to C3. 



The structure of Warfarin

Warfarin is optically active, and from the time of it’s discovery it was recognised that the two enantiomers were clinically different in their effect as a drug. So establishing the absolute configuration of the two isomers was a priority.


R-warfarin 2D


S-warfarin 2D

Hemiketal Ring Formation


RR-warfarin 2D


SS-warfarin 2D


RS-warfarin 2D


SR-warfarin 2D

The stereochemical assignment of (−)-(S)-warfarin was initially achieved by relating it to (−)-(R)-beta-phenylcaproic acid through a series of reactions not involving the asymmetric center {B.D.West, S.Preis, C.H.Schroder, & K.P.Link, J.Amer.Chem.Soc.,1961,83, 2676}. This assignment was confirmed by a determination of the crystal and molecular structure, and using the anomalous scattering of oxygen, and absolute configuration of (−)-(S)-Warfarin was measured {E.J.Valente, W.F.Trager and L.H.Jensen, Acta Cryst. 1975. B31, 954}.

The Hemiketal

The primary feature of the structure of (−)-warfarin is the hemiketal ring formed by cyclization of the side-chain keto function and the phenolic hydroxyl in the 4 position of the coumarin ring system. The crystal structure of racemic warfarin has the same feature. In solution n.m.r. spectra shows that the hemiketal is present in acetone solution.

Bond Lengths

The hemiketal bonding is rather weak. Thus the bond lengths within the hemiketal show that the atoms retain some of the characteristic of an open side chain keto group.

The Absolute Configuration

In the open chain keto form warfarin has two isomers, R andS, however the hemiketal introduces a second assymmetric center, so that we can have RR,SS, RS, and SR forms. The crystal structure determination favoured the SS enantiomer in the crystal studied.

Enantiomers & Biochemical Function

The S-isomer is very much more potent than the R isomer in both rats and humans.The S-isomer is stereoselectively oxidized to the inactive 7-hydroxywarfarin, and the keto-group of the R-isomer is stereospecifically reduced to the slightly active R,S-alcohol. Both isomers are oxidized to the inactive 6-hydroxywarfarin.

It is evident that we are dealing with a very complex system indeed; the presence of the hemiketal adds four more enantiomers to the complexity pot. Recent work has unravelled some more of the mechanisms behind the Vitamin K1 antagonism of Warfarin.

Preparation of Coumarins: the Pechmann Condensation

In 1883 Hans von Pechmann and Carl Duisberg {H. v Pechmann, and C. Duisberg, Ber., 1883, 16, 2119} found that phenols condense with beta-ketonic esters in the presence of sulphuric acid, giving coumarin derivatives.

Pechman condensation for coumarin synthesis

With R1=OH we have 4-hydroxycoumarin, the starting material for the preparation of Warfarin

The reaction is also catalysed by the presence of a Lewis acid such aluminium(III) chloride or other strong Brönstedt acids such as methanesulphonic acid to form a coumarin. The acid catalyses trans-esterification as well as keto-enol tautomerisation.

Bismuth(III) chloride, also a Pechmann catalyst, provides a recent procedure for 4-substituted coumarins.{ An Efficient and Practical Procedure for the Synthesis of 4-Substituted Coumarins Surya K. De*, Richard A. Gibbs, Synthesis, 2005, 1231.}

In another Pechmann condensation synthesis, the ionic liquid 1-butyl-3-methylimidazolium chloroaluminate ([bmim]Cl.2AlCl3) plays the dual role of solvent and Lewis acid catalyst for the reaction of phenols with ethyl acetoacetate leading to coumarin derivatives. Here, the reaction time is reduced drastically even at ambient conditions. {M. K. Potdar, S. S. Mohile, M. M. Salunkhe, Tetrahedron Lett., 2001, 42, 9285}

Solid acid catalysts with the H+ attached to the polymer surface such as Nafion 417 or Amberlyst IR120 can be used. Thus resorcinol reacts with ethyl acetoacetate in boiling toluene in the presence of Nafion sheet to form the coumarin 7-hydroxy-4-methylcoumarin. This preparation forms the basis of a student organic chemistry experiment at Penn State University. In this case the coumarin, {also named, 7-hydroxy-4-methyl-2H-benzo[b]-pyran-2-one} is not a blood thinner but is a drug used in bile therapy, Hymecromone. The material is also, in highly purified form a laser dye, and the starting material for some insecticides!

The Preparation of Warfarin

warfarin synthesisReaction of 4-hydroxycoumarin with benzylacetone underMichael reactionconditions gives racaemic warfarin.

assymetric synthesis via MacMillan catalyst
Imidazolidinone compounds – MacMillan organocatalysts – enable a stereoselective preparation for this reaction
There has been a recent flurry of interest in such assymetric preparation, well cataloged byWikipedia, references 17 to 22. The last reference even puts the stereoselective preparation into the second year undergraduate chemistry laboratory as an innovative ‘green chemistry’ experiment:

The enantioselective synthesis of drugs is of fundamental importance in the pharmaceutical industry. In this experiment, students synthesize either enantiomer of warfarin, a widely used anticoagulant, in a single step from inexpensive starting materials. Stereoselectivity is induced by a commercial organocatalyst, (R,R)- or (S,S)-1,2-diphenylethylenediamine. The environmentally friendly microscale reaction is performed at ambient temperature, and the product can be purified by recrystallization or column chromatography. Product characterization includes thin-layer chromatography, NMR spectroscopy, and polarimetry. {T.C.Wong, C.M.Sultana and D.A.Vosburg, Department of Chemistry, Harvey Mudd College, Claremont, California 91711, J. Chem. Educ., 2010, 87(2), 194}

The Biochemistry of Warfarin Action

This is a complex biochemical and medical subject, certainly beyond the simple chemistry required for a molecule of the month! Warfarin acts as a Vitamin K antagonist, that is it blocks the action of vitamin K epoxide reductase.

Vitamins K1 and K2

This vitamin is found in brassicas, spinach, parsley, and other green vegetables, avocado pairs are also rich in Vitamin K1.

For Vitamin K2, n signifies a number of five-carbon side chain units, hence MK-n, and except for MK4, is synthesised by gut bacteria. Both vitamins are fat soluble, the “K” deriving from the German “koagulation”. German researchers discovered the K vitamins, and that they are involved in blood clotting.

Vitamin K Cycle

gammacarboxyglutamateVitamin K is a cofactor in the synthesis of blood clotting factors II, VII, IX and X*, this step occurs in the liver and involves the gammacarboxylation of the first 10 glutamic acid residues in the amino-terminal region of the prothrombin clotting factor to generategamma-carboxyglutamate. The gamma-carboxyglutamatee amino acid groups can chelate Ca2+ better than ten replaced glutamate residues, thus providing binding sites for four Vitamin Ks onto the phospholipid membrane during coagulation. The clotting occurs via a cascade*, a kind of biochemical chain reaction. {See Biochemistry by Stryer for the terminology}

Vitamin K cycleTo work, the Vitamin K must be reduced to its quinol or hydroquinone form. This is achieved with Vitamin K Oxide reductase, which is the step inhibited by S-warfarin, being some three times more potent than R-warfarin. S-warfarin is metabolized primarily by the CYP2C9 enzyme of the cytochrome P450 system. The R-warfarin is metabolized by the two cytochrome P450 enzymes, CP1A4Y and CYP3A4. Warfarin is very soluble in water, and is absorbed into the blood stream within 90 minutes of taking the pills.

So far as the enantiomers are concerned, racaemic warfarin has a half life of around 40 hours, the two enantiomers, having half lives: R-warfarin, 45 hours; S-warfarin, 29 hours.

During my review for MoTM, necessarily hurried, I have not been able to find out if the hemiketal, with the four enantiomers is involved. That the hemiketal is weak is shown by the crystal structure study, so, in any case these enantiomers will have short half lives. It all adds to the complexity.

The relationship between the dose of warfarin and the response is modified by genetic and environmental factors that can influence the absorption of warfarin, its pharmacokinetics, and its pharmacodynamics.

An application of an asymmetric synthesis with a DuPhos ligand is the hydrogenation of dehydrowarfarin to warfarin:[9]

Warfarin synthesis

The first practical asymmetric synthesis of R and S-Warfarin Andrea Robinson and Hui-Yin Li John Feaster Tetrahedron Letters Volume 37, Issue 46, 11 November 1996, Pages 8321-8324doi:10.1016/0040-4039(96)01796-0

Links & References

  1. Biochemistry, Lubert Stryer, Freeman and Co. 1981; the basics of blood clotting are described in Chapter 8.
  2. The Crystal and Molecular Structure and Absolute Configuration of (−)(S)-Warfarin, E.J.Valente, W.F.Trager and L.H.Jensen, Acta Cryst. 1975. B31, 954. A seminal paper on the structure of S-warfarin
  3. Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and Unsaturated Ketones – A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant, N.Halland, T.Hansen and K.A.Jørgensen, Angew. Chem. Int. Ed. 2003, 42(40), 4955.
  4. Studies on 4-Hydroxycoumarins. V. The Condensation of alpha,beta-Unsaturated Ketones with 4-Hydroxycoumarin. M. Ikawa, M.A. Stahmann and K.P.Link, J.Amer.Chem.Soc 1944, 66, 902.
  5. Pharmacology and Management of the Vitamin K Antagonists, an excellent and freely downloadable, CHEST article from a group of doctors and pharmacologists.
  6. Vitamin K: paper for students
  7. Vitamin K: Linus Pauling Institute article.
  8. Warfarin by Yunas Bhonoah of Imperial College. A student project. The crystal structure paper was not found, nor the differing effects of the two enantiomers. However see the section on themechanism of action of Warfarin
  9. Pharmacogenetics of warfarin elimination and its clinical implications. A paper dealing with pharmacogenetic polymorphism of cytochrome P450

//////////////////////Continuous Flow,  Stereoselective Synthesis, (S)-Warfarin, FLOW CHEMISTRY, FLOW SYNTHESIS

Flow Chemistry Symposium & Workshop 16-17 June at IICT, Hyderabad, India



2-day FLOW CHEMISTRY Symposium + Workshop has been organized on 16-17 June 2016 at

IICT Hyderabad, India   by Flow Chemistry Society – India Chapter (in collaboration with IICT-Hyderabad & IIT-B)

with speakers from India, UK, Netherlands and Hungary.

Both days have intensive interactive sessions on the theory and industrial applications of Flow Chemistry followed by live demonstrations using 7 different Flow Reactor platforms — from microliters to 10,000 L/day industrial scale.

The Fees are Rs. 5,000 for Industry Delegates and Rs. 2,500 for Academic Delegates (+15% Service Tax) : contact : or

I have attached a detailed program and look forward to meeting you at the event..


Vijay Kirpalani

Best regards

Vijay Kirpalani
Flow Chemistry Society – India Chapter
email :
Tel: +91-9321342022 // +91-9821342022


IICT, Hyderabad, India

Dr. S. Chandrasekhar,

CSIR-Indian Institute of Chemical Technology (IICT)

Hyderabad, India


Vijay Kirpalani

Mr Vijay Kirpalani

Flow Chemistry Society – India Chapter, INDIA

Charlotte Wiles

Dr Charlotte Wiles , CHEMTRIX




Prof. Anil Kumar

Prof Anil Kumar( IIT-B), INDIA


Manjinder Singh

/////Flow Chemistry, Symposium,  Workshop,  16-17 June, IICT, Hyderabad, India

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Abstract Image

Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

Two examples out of several in the publication discussed below……………

1  Diphenhydramine Hydrochloride

Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride
Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.
In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.
The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Scheme 2. Continuous Flow Synthesis of Olanzapine
Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.
In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd2dba3 as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H2O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et3SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.
The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)4 as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.


Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00325
Publication Date (Web): November 26, 2015
Copyright © 2015 American Chemical Society

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.

Riccardo Porta

Riccardo Porta

 PhD Student
Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Map of milan italy


Flow Chemistry India 2016, 21-22 January 2016, Mumbai, India

Flow Chemistry India 2016

Date: Thursday, 21 January 2016 Friday, 22 January 2016
Location: Mumbai, India




Hotel Ramada Powai and Convention Centre, Mumbai, India

Paul Watts

Professor & Research Chair, Nelson Mandela Metropolitan University

Shu Kobayashi

Professor, Synthetic Organic Chemistry , The University of Tokyo

Vivek Ranade

Deputy Director and Chair, National Chemical Laboratory

Volker Hessel

Professor, Eindhoven University of Technology

Claude de Bellefon

Scientific Director, University of Lyon

Ferenc Darvas

Chairman, Flow Chemistry Society

Marek Trojanowicz

Professor, University of Warsaw




Pooja Sharma and Sakshi Modgil,


Garima Sharma

 Maninderjit Singh Ahluwalia


SELECTBIO INDIA is delighted to welcome you all at the 4th International Conference Flow Chemistry India 2016 to be held in Mumbai on January 21-22, 2016 under the auspices of the Flow Chemistry Society.  The society aims to unite and represent those who are actively working on this rapidly developing field. This meeting is dedicated to the integration of flow chemistry into everyday practice throughout the world by delivering the latest knowledge and making it available for the entire chemistry community.

Society members save 25% on the registration fee and non-members will receive their first year’s membership included in the fee.

Running alongside the conference will be an exhibition covering the latest technological advances in the area of flow chemistry.

Who Should Attend

• Scientists, Chemists, Chemical Engineers and Researchers working in Pharmaceutical and Fine Chemicals Research and Development including Drug Discovery, Medicinal Chemistry and Chemical Process Development

• Scientists, Chemists and Chemical Engineers working in Pharmaceutical and Fine Chemical Bulk Manufacturing Units

• Corporate Management, Scientists, Managers responsible for development of Pharmaceutical and Fine Chemicals R & D and Manufacturing activities

• Scientists, Chemists & Engineers belonging to the fields of Inorganic, Organic, Medicinal, Natural Products, Analytical, High-throughput and Process Chemistry in the Academic research as well as in Applied research and development in the area of Agrochemical, Petrochemical and Fragrance industry

• Scientists working in or interested in applications of Flow Chemistry in Material science, Green chemistry, Nanotechnology, Biotechnology, Theoretical Chemistry, Information technology and Flow synthesis instruments including Engineering & Automation

Conference Package – Includes Registration, 2 Nights Accommodation, Dinner & Airport Transfers (Valid up to January 5, 2016 only)

Call for Posters

You can also present your research on a poster while attending the meeting. Submit an abstract for consideration now!

Poster Submission Deadline: 30 November 2015

Agenda Topics

  • Advances in Micro & Continuous Flow Reactors, Systems & Processes
  • Applications in Pharmaceutical Industry & API Synthesis
  • Engineering Aspects of Flow Chemistry
  • Flow Reactor – Choosing the Right One
  • Photochemistry & Multistep Synthesis in Flow
  • Quality Issue and QbD in Flow Chemistry
  • Scale up – From Micro to Commercial Scale
  • Yield Improvement, Cost Cutting and Waste Reduction in Flow Chemistry

Sponsorship and Exhibition Opportunities

Maninderjit Singh, Exhibition Manager



Workshop Tutor

Charlotte Wiles


A Workshop on “Flow Chemistry Demonstrations (Lab & Plant Scale) for Chemical and Pharmaceutical Industry-” will be held one day prior to the training course i.e. on 20th January, 2016 from 10:00 am – 05:00 pm in Mumbai. This workshop is supported by Process Intensification will be jointly conducted by :

Dr. Dinesh Kudav (Mumbai University); Dr. Charlotte Wiles (Chemtrix BV-Neth);  Mr. Wouter Stam (Flowid, NV-Neth); Mr. Manjinder Singh (CIPLA & VP-FCS-India Chapter);  Dr. Viktor Gyollai, (AM Technology-UK);  Dr. Prashant Kini (UPL Ltd.); Mr. Kumar Oza (Pi & TCPL);  Mr. Madhav Sapre (Pi & Sharon Bio); et al .

This workshop is specially designed to demonstrate application/capabilities of  Flow Chemistry running “live” reactions in Continuous Flow Reactors. The reactions likely to be demonstrated using Flow Chemistry includes :• Nitration • Organometallic reaction• Oxidation • Bi-phasic reaction• Nano-Particle preparation in Flow• Biocatalytic Reaction with enhanced enzyme life.

This workshop is free for the registered delegates of Flow Chemistry India 2016 Conference and Continuous Flow Reactors Training Course.

You can visit Mumbai city

Taj hotel, mumbai

Gateway of india

Food in mumbai

mumbai skyline

The Bandra-Worli Sea Link is a cable-stayed bridge that connects central Mumbai with its western suburbs



 get in if you can

 The Mumbai Suburban Railway system carries more than 6.99 million commuters on a daily basis. It has the highest passenger densities of any urban railway …



Chhatrapati shivaji in mumbai india

British-victoria terminus




A PdCl2-Based Hydrogenation Catalyst for Glass Microreactors

A PdCl2-Based Hydrogenation Catalyst for Glass Microreactors

Journal Journal of Flow Chemistry
Publisher Akadémiai Kiadó
ISSN 2062-249X (Print)
2063-0212 (Online)
Subject Flow Chemistry
Issue Volume 4, Number 3/September 2014
Pages 110-112
DOI 10.1556/JFC-D-13-00036
Clemens R. Horn1 Email for, Carine Cerato-Noyerie

17bis avenue de Valvins Corning European Technology Center F- 77210 Avon France


A convenient and simple PdCl2-based hydrogenation catalyst has been developed. The liquid, air, and moisture stable precursor is pumped into the reactor where it is temporarily immobilized and reduced on the channel surface into Pd(0), providing a constant high activity for hydrogenation reaction. The catalyst is leached with time, avoiding any kind of clogging problems during long time runs.



Map of Corning SAS

7 Bis Avenue de Valvins, 77210 Avon, France

lyon france

Continuous Flow Synthesis of alpha-Halo Ketones: Building Blocks for Anti-retroviral Agents

Chiral alpha-halo ketones derived from N-protected amino acids are key building blocks for the synthesis of HIV protease inhibitors such as atazanavir used in HAART combination therapy.

Kappe and De Souza have reported a continuous flow through route to these intermediates which utilises a tube-in-tube reactor to introduce diazomethane generated on demand into the reaction stream containing mixed anhydride derivatives of N-protected amino acids. The resulting alpha-diazo ketones are then decomposed with HCl or HBr to afford the corresponding alpha-halo ketones.

This process allows the safe generation, separation and use of diazomethane in a continuous integrated multi-step synthesis of important API intermediates.

Abstract Image

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor.

The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber.

The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide.

This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ∼4.5 h (87% yield).

Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.

tetrazole synthesis

Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.

B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, J. Flow Chem. 2012, 2,8-19.

Bernhard Gutmann1, David Obermayer1, Jean-Paul Roduit2, Dominique M. Roberge2 Email for, C. Oliver Kappe2 Email for

1Christian Doppler Laboratory for Microwave Chemistry and Institute of Chemistry, Karl-Franzens-University Graz A-8010 Heinrichstrasse 28 Graz Austria
2Microreactor Technology, Lonza AG CH-3930 Visp Switzerland


Hydrazoic acid (HN3) was used in a safe and reliable way for the synthesis of 5-substitued-1H-tetrazoles and for the preparation of N-(2-azidoethyl)acylamides in a continuous flow format. Hydrazoic acid was generated in situ either from an aqueous feed of sodium azide upon mixing with acetic acid, or from neat trimethylsilyl azide upon mixing with methanol.


For both processes, subsequent reaction of the in situ generated hydrazoic acid with either organic nitriles (tetrazole formation) or 2-oxazolines (ring opening to β-azido-carboxamides) was performed in a coil reactor in an elevated temperature/pressure regime. Despite the explosive properties of HN3, the reactions could be performed safely at very high temperatures to yield the desired products in short reaction times and in excellent product yields.


The scalability of both protocols was demonstrated for selected examples. Employing a commercially available benchtop flow reactor, productivities of 18.9 g/h of 5-phenyltetrazole and 23.0 g/h of N-(1-azido-2-methylpropan- 2-yl)acetamide were achieved.

flow chemistry, hydrazoic acid, microreactor, process intensification, tetrazoles

Pi-Process Intensification Experts LLP at CPhI Mumbai India 3rd Dec 2014…My visit


I (Dr Anthony) seated with Dr Vijay Kirpalani CEO of Pi-Process Intensification Experts LLP
at CPhI Mumbai India 3rd Dec 2014
Pi-Process Intensification Experts LLP

Process Intensification

Creating competitive advantage through Improved and consistent quality, high efficiencies and maximum flexibility.

Safer, Cleaner, Smaller, Cheaper and Smarter processes , The basic principle of Process Intensification is to fit the equipment to the process and not process to the equipment, as is the case now.

Process Intensification can achieve drastic improvement in the time cycle and yields as well as converting batch processes to continuous process using specialized set of equipment. The design philosophy in process intensification is to design a process which has Chemical Kinetics as its only limitation. See the illustration below

“Process Intensification by Kinetics alone controlling the reaction, using specialized equipments; modification / telescoping of process steps achieves drastic reduction in time cycles and converts batch processes to continuous ; Reduced energy consumption, Reduced by-product formation; sustainability , hazard-containment, compliance to QbD and PAT and importantly a much faster time-to-market”

Illustrative examples are as follows:

  • Watt’s aldol reaction: Time needed to reach 100 % conversion 20 minutes against 24 hours in batch process
  • Fisher Esterification: Pi gives 83% yield against 15% in batch process
  • Grignard Reaction: Pi gives 78% yield against 49% in batch process
  • Nitration Reaction: Product purity increase from 56% to 78% and yield of mononitrate increases 55% to 75%.
Benefits of Process Intensification (PI) Techniques

Benefits of Process Intensification (PI) Techniques

Sponsored Projects

Scale-up for Retrofitting in existing plant as well as greenfield projects based on flow chemistry data generated in our laboratory. A well-equipped Laboratory and Pilot Plant set-up is available at our “Pi-Lab” for carrying out “FLOW Chemistry” based Reactions and utilizing numerous Process Intensification techniquesfor Unit-Processes & Unit-Operations for the industry to reap the benefits of Process Intensification.

The laboratory and pilot plant data will be utilized to provide the plant scale design using specialized equipments like micro-reactors, micro-plate-reactors in SiC, monolithic loop reactors, spinning disk reactors-cum-heat exchangers, FUMI reactors, dynamic mixing reactors, oscillatory baffled reactors (OBR), Bio-catalytic impregnated membrane Reactors, and other modern state-of-the-art equipments enabling conversion of batch to continuous flow processes.

We handle hazardous chemistries with very high exotherms (upto 1300 J/gm) safely in the range of -70oC to + 250oC with pressures upto 200 bar, and with reaction times from 0.03 sec to 1 hour and reactor volumes from 0.2 ml to 100 ml (Lab) and 1 L (Pilot) — yielding from 20 gms to 8 Kgs/hour (Lab) and 500 gms to 200 Kgs/hour (Pilot).

Scale Up – Flexibility & Adaptability

Pi …… will provide all the services for scale up to the sizes desired by clients by utilizing data from Laboratory trials.


A range of Flow Chemistry and Process Intensification equipments can be offered on rent. This enables the users to get the hands-on experience so as to select the apt equipments for their needs.

Vijay Kirpalani
Pi-Process Intensification Experts LLP
Plot-W-33,  M.I.D.C. Industrial Area
TALOJA – 410208, Navi Mumbai, INDIA
email :
Tel: +91-9321342022 // +91-9821342022

some pics from hall 5 -H-47 at cphi mumbai india dec 3 2014







A Flow Reactor with Inline Analytics: Design and Implementation


A Flow Reactor with Inline Analytics: Design and Implementation

Org. Process Res. Dev., 2014, 18 (11), pp 1315–1320
DOI: 10.1021/op5002512
pp 1315–1320
Publication Date (Web): October 13, 2014 (Article)
DOI: 10.1021/op5002512
A continuous flow system complete with inline analytics is described. Sampling from a high pressure reactor and automated delivery mechanisms are detailed. The ability of the system to maintain critical process parameters (CPP) throughout a reaction process is demonstrated. Setup performance was evaluated using the Claisen rearrangement of allyl phenyl ether (1).
Flow synthesis has garnered industrial interest from the promise of reducing wasteful and inefficient batch-manufacturing process development(1) by replacing the conventional “scale up” approach with “scale out” continuous production.(2) The development of synthetic protocols to supply material for early phase discovery (medicinal chemistry), formulation, and clinical trials consumes significant time and resources and carries a high cost.(3) Further, the effort put into developing a robust and compliant batch scale-up methodology goes for naught if the active pharmaceutical ingredient (API) ultimately fails later stage trials. By developing a flow process early on, any amount of product required may be obtained by running the flow system with the same conditions for the appropriate length of time. The promise of flow technology is that, once optimized, a process remains viable through the entire drug development process. Furthermore, quality by design (QbD) can be facilitated by flow synthesis because of the ability to closely monitor and control CPPs (those parameters “whose variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality,” e.g., temperature, flow rate, stoichiometry; “where a CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality,”(4) e.g., yield, impurity) during a run.(5) Ultimately, flow-reactor technology will be employed for full-scale commercial API production.(6)
  • 1.

    Wu, H., Dong, Z., Haitao, L., and Khan, M. Org. Process Res. Dev. 2014, 18, 10.1021/op500056a.

  • 2.

    (a) Razzaq, T.; Kappe, C. O. Chem.—Asian J. 2010, 5, 12741289

    (b) Wiles, C.; Watts, P. Green Chem. 2014, 16, 5562

    (c) Moseley, J. D.; Woodman, E. K. Org. Process Res. Dev. 2008, 12, 967981

  • 3.

    Ullah, F.; Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.; Organ, M. G. Chem.—Eur. J. 2010, 16, 1095910962

    and references cited therein

  • 4.

    Guidance for Industry, Q8(R2) Pharmaceutical Development; U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research: Silver Springs, MD, 2009; p 18.

  • 5.

    Calibrese, G. S.; Pissavini, S. AIChE J. 2011, 54, 828834

  • 6.

    (a) Alsten, J. G.; Reeder, L. M.; Stanchina, C. L.; Knoechel, D. J. Org. Process Res. Dev. 2008, 12, 989994

    (b) Roberge, D. M.; Zimmermann, B.; Rainonee, F.; Gottsponer, M.; Eyholzer, M.; Kockmann, N. Org. Process Res. Dev. 2008, 12, 905910

Vijay Kirpalani

Vijay Kirpalani


Pi-inc (Process Intensification Experts LLP)


Toronto, canada

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