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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , 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 goflow.at online! from C. Oliver Kappe, University of Graz


New Website goflow.at 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: goflow.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.

apis


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

DR SANJAY BAJAJ,,,,,,,,,,,,,,,,,,,DR ANTHONY CRASTO…………PROF OLIVER KAPPE FLOW CHEM CONFERENCE , MUMBAI, 22 JAN 2015……SELECTBIO

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

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Flow synthesis of Meclinertant


SR-48692 structure.png

SR48692 (Meclinertant)

Reminertant; SR 48692

CAS [146362-70-1]

  • Molecular FormulaC32H31ClN4O5
  • Average mass587.065

SEE…...https://newdrugapprovals.org/2014/12/31/meclinertant-sr48692/

2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid

  • Originatorsanofi-aventis
  • ClassAnalgesics; Antineoplastics; Antipsychotics
  • Mechanism of ActionNeurotensin antagonists

ChemSpider 2D Image | Meclinertant | C32H31ClN4O5

Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS1, and was the first non-peptide antagonist developed for this receptor.[1][2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,[3][4][5][6][7][8] and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.[9][10][11][12]

CLIP

Methods for the synthesis of pharmaceuticals have improved over the years, however, the technology and tools used to perform synthetic operations have remained the same. Batch-mode processes are still common but many improvements can be made by using modern technologies. Recently, the use of machine-assisted protocols has increased, with flow-based chemical synthesis being extensively investigated. Under dynamic flow regimes, mixing and heat transfer can be more accurately controlled, the use of solid-phase reagents and catalysts can facilitate purification, and tedious downstream processes (workup, extraction, and purification) are reduced.
Steven V. Ley and co-workers, University of Cambridge, UK, have been evaluating the utility of flow-based syntheses to accelerate multistep routes to highly complex, medically relevant compounds, in this case Meclinertant (SR48692, pictured). They show that new technologies can help to overcome many synthetic issues of the existing batch process. In this case, flow chemistry has allowed control of exothermic events, controlled the superheating of solvents, and streamlined the synthesis by allowing reaction telescoping. It has also helped to prevent back mixing and the accumulation of byproducts. The use of polymer-supported reagents has simplified downstream processing and enhanced the safety of reactions, and in-line monitoring can track hazardous intermediates.

These new technologies have been shown to be powerful synthetic tools, although care must be taken not to convert them to expensive solutions to nonexistent problems.

http://community.dur.ac.uk/i.r.baxendale/papers/ChemEurJ2013.19.7917.pdf

A Machine-Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor-1,
Claudio Battilocchio, Benjamin J. Deadman, Nikzad Nikbin, Matthew O. Kitching, Ian R. Baxendale, Steven V. Ley,
Chem. Eur. J. 2013.
DOI: 10.1002/chem.201300696

2-[1-(7-Chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido]adamantane-2-carboxylic acid (1):

Polymer-supported sulfonic acid (QP-SA; 0.6 g, 2.4 mmol) was added to a solution of tert-butyl 2-[1- (7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido]adamantane-2-carboxylate (13; 30 mg, 0.05 mmol) in dichloromethane and the reaction was stirred at RT for 18 h. The QP-SA was filtered off and the filtrate concentrated in vacuo to provide the title compound as white crystals (yield 25 mg, 0.04 mmol, 86%).

M.p. 219–222 deg C;

1 H NMR (400 MHz, CDCl3, 25 deg C): d=8.91 (d, 1H, J=4.6 Hz), 8.15 (d, 1H, J=2.1 Hz), 7.78 (d, 1H, J=9.1 Hz), 7.68 (dd, 1H, J=2.1, 9.1 Hz), 7.28 (d, 1H, J=4.7 Hz), 7.24 (t, 1H, J=8.5 Hz), 7.91 (s, 1H), 6.52 (d, 2H, J=8.5 Hz), 3.42 (s, 6H), 2.64–2.56 (m, 2H), 2.17–2.05 (m, 2H), 2.04–1.92 (m, 2H), 1.82–1.71 (m, 2H), 1.71–1.61 (m, 4H), 1.61–1.50 ppm (m, 2H); 

13C NMR (100 MHz, CDCl3, 25 deg C): d=173.3(C), 159.9 (C), 157.5 (C), 157.5 (C), 151.8 (CH), 149.1 (C), 143.4 (C), 139.2 (C), 134.8 (C), 131.9 (CH), 128.0 (CH), 127.7 (CH), 125.9 (CH), 122.2 (C), 118.6 (CH), 109.6 (CH), 105.8 (C), 104.0 (CH), 55.4 (CH3), 55.3 (C), 37.4 (CH2), 33.6 (CH2), 32.8 (CH2), 31.9 (CH), 26.5 (CH), 26.2 ppm (CH);

FT-IR (neat): 3405, 2922, 1728, 1674, 1591, 1527, 1474, 1433, 1379, 1357, 1288, 1251, 1206, 1101, 1077, 1031, 1006, 957, 882, 865, 823, 779, 725, 682 cm1 ;

LCMS: tR =5.29 min, m/z [M+H]+: 587.46;

HRMS (ESI): m/z calcd for C32H32N4O5Cl+: 587.2061, found 587.2053; the structure was unambiguously confirmed by single X-ray crystallography; space group P1¯: a= 10.249, b=11.718, c=12.634 ; a=76.6, b=72.9, g=76.4o

CLIP AND ITS OWN REFERENCES

Although batch processes remain the most used procedure for running chemical reactions, the use of machine-assisted flow methodologies(24) enables an improved efficiency and high throughput. A direct comparison between conventional batch preparation and flow multistep synthesis of selective neurotensine probe SR48692 (Meclinertant) was reported by Ley and co-workers in 2013 (Scheme 6).(25)

In this case study, the authors investigated whether flow technology could accelerate a multistep synthesis (i.e., higher yields or lower reaction times) and overcome many synthetic issues (i.e., solid precipitation or accumulation of byproducts). The initial Claisen condensation between ketone 31 and ethyl glyoxalate in the presence of NaOEt as base and EtOH as solvent in batch is run at room temperature and product 32 is obtained in 60% yield after 3 h stirring.

Superheating (heat above solvent boiling point) the reaction in flow provided a faster alternative: using a 52 mL PFA reactor coil at 115 °C with a residence time of 22 min gave the corresponding product 32 in 74% yield. In order to solve some problems of solid accumulation an ad-hoc pressurized stainless-steel tank (5 bar, nitrogen) was designed; it allowed to run the reaction continuously without any precipitation or blockage.

Figure

The following reaction between 32 and commercially available hydrazine 33 was performed in DMF in the presence of concentrated H2SO4. After 52 min of residence time at 140 °C into a 52 mL PFA reactor coil the crude mixture was treated with an Na2CO3 aq. and then inline extracted through a semipermeable membrane with CH2Cl2. After crystallization, pyrazole ester 34 was isolated in 89% yield.

The corresponding reaction in batch was conducted in DMF under microwaves irradiation at 140 °C for 2 h. Running the reaction in batch on the same scale as in flow (3.58 mmol) gave product 34 in a lower yield (70%). The subsequent hydrolysis was performed combining a THF solution of ester 34 and 3 M aqueous KOH. The reaction was performed inside a 14 mL PFA reactor coil heated at 140 °C with a residence time of 14 min.

Upon treatment with 3 M HCl aq., acid 35 precipitated, and it was isolated by filtration in 90% yield. In this case, the corresponding batch hydrolysis afforded product 35 with the same yield (90%); however, a longer reaction time (1.5 h) was required. The final amide formation was performed by reacting acid 35 (activated as acyl chloride) and protected amino alcohol 37through a telescoped synthesis. Triphosgene 36 (a safer substitute for phosgene) was found to be the best acid activator.

Triphosgene decomposition occurred in the presence of DIPEA at 100 °C into a stainless steel heat exchanger, where phosgene was generated. The crude mixture, containing also acid 35, then passed into a 2.5 mL stainless steel reactor coil at 25 °C, to complete the formation of the corresponding acyl chloride. An inline Flow-IR spectrometer(26)was used to monitor the formation of phosgene without exposing the operator to the toxic gas during analysis. As soon as acyl chloride was formed it was reacted with protected amino alcohol 37.

The amide formation took place into a 14 mL stainless steel reactor coil at 100 °C with a residence time of 75 s. Amide 38 was isolated in 85% yield after quenching with NH4Cl and extraction with AcOEt. For obvious safety concerns, avoiding the handling of phosgene and the isolation of highly reactive acyl chloride intermediate represent a remarkable improvement with respect to batch procedure.

Finally, meclinertant 39 was obtained after deprotection of ester38 by using a polymer-supported sulfonic acid. The last synthetic step was conducted in batch on a small scale; however, it could be easily transferred to flow mode by using a column packed with commercially available polymer-supported sulfonic acid.

24 Ley, S. V.; Fitzpatrick, D. E.; Myers, R. M.; Battilocchio, C.; Ingham, R. J. Angew. Chem., Int. Ed. 2015, 54, 2, DOI: 10.1002/anie.201501618

25.Battilocchio, C.; Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale, I. C.; Ley, S. V. Chem. – Eur. J. 2013, 19, 7917, DOI: 10.1002/chem.201300696

Org. Process Res. Dev., 2016, 20 (1), pp 2–25
DOI: 10.1021/acs.oprd.5b00325

CLIP AND ITS OWN REFERENCES

The choice of the flow reactor also plays a key role in the synthesis of meclinertant (SR48692, 103), which is a potent probe for investigating neurotensin receptor-1 [92]. The flow synthesis of this challenging compound was reported in 2013 and aims to evaluate the benefits of flow chemistry in order to avoid shortcomings of previous batch synthesis efforts particularly in regard to scale up [93].

The investigation first involved the preparation of the key acetophenone starting material 112 which although commercially available was expensive and could be generated from 1,3-cyclohexadione (104). The sequence consisted of O-acetylation, a Steglich rearrangement, oxidation and a final methylation reaction.

As the use of flow chemistry had already improved the O-acetylation during scale-up tests (130 mmol) by avoiding exotherms, it was anticipated that the subsequent Steglich rearrangement could be accomplished in flow using catalytic DMAP instead of stoichiometric AlCl3 as precedented (Scheme 19).

This was eventually realised by preparing a monolithic flow reactor functionalised with DMAP that proved far superior to commercially available DMAP on resin. Employing the monolithic reactor cleanly catalysed the rearrangement step when a solution of 106 was passed through the reactor at elevated temperature (100 °C, 20 min residence time).

The resulting triketone 107 was telescoped into an iodine mediated aromatisation, followed by high temperature mono-methylation using dimethyl carbonate/dimethylimidazole as a more benign alternative to methyl iodide at scale.

[1860-5397-11-134-i19]
Scheme 19: First stage in the flow synthesis of meclinertant (103).

The subsequent Claisen condensation step between ketone 112 and diethyl oxalate (113) was reportedly hampered by product precipitation and clogging problems, thus a pressure chamber was developed [94] that would act as a pressure regulator allowing this step to be scaled up in flow in order to provide 114 on multigram scale (134 g/h).

A Knorr pyrazole formation between 114 and commercially available hydrazine 115 had previously been found difficult to scale up in batch (the yield dropped from 87% to 70%) and was thus translated into a high temperature flow protocol (140 °C) delivering the desired product 116 in 89% yield (Scheme 20).

Ester hydrolysis and a triphosgene (118) mediated amide bond formation between acid 117 and adamantane-derived aminoester119 [95] completed this flow synthesis. Meclinertant (103) was subsequently obtained after batch deprotection using polymer supported sulfonic acid.

Overall, this study showcases how flow chemistry can be applied to gain benefits when faced with problems during mesoscale synthesis of a complex molecule. However, despite the successful completion of this campaign, it could be argued that the development time required for such a complex molecule in flow can be protracted; therefore both synthetic route and available enabling technologies should be carefully examined before embarking upon such an endeavour.

[1860-5397-11-134-i20]
Scheme 20: Completion of the flow synthesis of meclinertant (103).
92   Myers, R. M.; Shearman, J. W.; Kitching, M. O.; Ramos-Montoya, A.; Neal, D. E.; Ley, S. V. ACS Chem. Biol. 2009, 4, 503–525. doi:10.1021/cb900038e
93. Battilocchio, C.; Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale, I. R.; Ley, S. V.Chem. – Eur. J. 2013, 19, 7917–7930. doi:10.1002/chem.201300696
94. Deadman, B. J.; Ley, S. V.; Browne, D. L.; Baxendale, I. R.; Ley, S. V.Chem. Eng. Technol. 2015, 38, 259–264. doi:10.1002/ceat.201400445
95. Battilocchio, C.; Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V.Org. Process Res. Dev. 2012, 16, 798–810. doi:10.1021/op300084z

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

Marcus BaumannEmail of corresponding author and Ian R. BaxendaleEmail of corresponding author
Department of Chemistry, Durham University, South Road, DH1 3LE Durham, United Kingdom
Email of corresponding author Corresponding author email
Associate Editor: J. A. Murphy
Beilstein J. Org. Chem.2015,11, 1194–1219.
EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493
The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.
Patent ID Date Patent Title
US8642566 2014-02-04 Therapeutic approaches for treating neuroinflammatory conditions
US7927613 2011-04-19 Pharmaceutical co-crystal compositions
US7790905 2010-09-07 Pharmaceutical propylene glycol solvate compositions
US2007243257 2007-10-18 PHARMACEUTICAL COMPOSITION COMPRISING A SOLID DISPERSION WITH A POLYMER MATRIX CONTAINING A CONTINUOUS POLYDEXTROSE PHASE AND A CONTINUOUS PHASE OF A POLYMER OTHER THAN POLYDEXTROSE
US6284277 2001-09-04 Stable freeze-dried pharmaceutical formulation
US6172239 2001-01-09 Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharamaceutical compositions containing them
US5965579 1999-10-12 Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5955474 1999-09-21 Use of neurotensin antagonists for the treatment of edematous conditions
US5939449 1999-08-17 Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5936123 1999-08-10 Hydrazine derivative compounds as intermediates for preparing substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors
Patent ID Date Patent Title
US5925661 1999-07-20 Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5744491 1998-04-28 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5744493 1998-04-28 3-amidopyrazole derivatives and pharmaceutical compositions containing them
US5723483 1998-03-03 Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them
US5635526 1997-06-03 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5616592 1997-04-01 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5607958 1997-03-04 3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them
US5585497 1996-12-17 Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin
US5561234 1996-10-01 1-(7-chloroquinolin-4-yl)pyrazole-3-carboxamide N-oxide derivatives, method of preparing them, and their pharmaceutical compositions
US5523455 1996-06-04 Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them
Patent ID Date Patent Title
EP0699438 1996-03-06 Use of neurotensin antagonists for the preparation of diuretic drugs Use of neurotensin antagonists for the preparation of diuretic drugs
US5420141 1995-05-30 3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them
Meclinertant
SR-48692 structure.png
Systematic (IUPAC) name
2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid
Identifiers
CAS Number 146362-70-1 Yes
PubChem CID 119192
IUPHAR/BPS 1582
UNII 5JBP4SI96H Yes
ChEMBL CHEMBL506981
Chemical data
Formula C32H31ClN4O5
Molar mass 587.064

References

  1. Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard JC, Poncelet M, Gueudet C, Heaulme M, Leyris R, Brouard A (January 1993).“Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor”. Proceedings of the National Academy of Sciences of the United States of America. 90 (1): 65–9. doi:10.1073/pnas.90.1.65. PMC 45600free to read. PMID 8380498.
  2.  Gully D, Jeanjean F, Poncelet M, Steinberg R, Soubrié P, Le Fur G, Maffrand JP (1995). “Neuropharmacological profile of non-peptide neurotensin antagonists”. Fundamental & Clinical Pharmacology. 9 (6): 513–21. doi:10.1111/j.1472-8206.1995.tb00528.x.PMID 8808171.
  3.  Rostene W, Azzi M, Boudin H, Lepee I, Souaze F, Mendez-Ubach M, Betancur C, Gully D (April 1997). “Use of nonpeptide antagonists to explore the physiological roles of neurotensin. Focus on brain neurotensin/dopamine interactions”. Annals of the New York Academy of Sciences. 814: 125–41. doi:10.1111/j.1749-6632.1997.tb46151.x. PMID 9160965.
  4. Jump up^ Jolas T, Aghajanian GK (August 1997). “Neurotensin and the serotonergic system”. Progress in Neurobiology. 52 (6): 455–68.doi:10.1016/S0301-0082(97)00025-7. PMID 9316156.
  5. Jump up^ Dobner PR, Deutch AY, Fadel J (June 2003). “Neurotensin: dual roles in psychostimulant and antipsychotic drug responses”. Life Sciences.73 (6): 801–11. doi:10.1016/S0024-3205(03)00411-9. PMID 12801600.
  6. Jump up^ Chen L, Yung KK, Yung WH (September 2006). “Neurotensin selectively facilitates glutamatergic transmission in globus pallidus”.Neuroscience. 141 (4): 1871–8. doi:10.1016/j.neuroscience.2006.05.049. PMID 16814931.
  7. Jump up^ Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (September 2008). “Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis”. Brain Research Bulletin. 77 (2–3): 129–35. doi:10.1016/j.brainresbull.2008.04.003. PMID 18721670.
  8. Jump up^ Petkova-Kirova P, Rakovska A, Zaekova G, Ballini C, Corte LD, Radomirov R, Vágvölgyi A (December 2008). “Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders”.Neurochemistry International. 53 (6–8): 355–61. doi:10.1016/j.neuint.2008.08.010. PMID 18835308.
  9. Jump up^ Griebel G, Moindrot N, Aliaga C, Simiand J, Soubrié P (December 2001). “Characterization of the profile of neurokinin-2 and neurotensin receptor antagonists in the mouse defense test battery”. Neuroscience and Biobehavioral Reviews. 25 (7–8): 619–26. doi:10.1016/S0149-7634(01)00045-8. PMID 11801287.
  10. Jump up^ Tirado-Santiago G, Lázaro-Muñoz G, Rodríguez-González V, Maldonado-Vlaar CS (October 2006). “Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats”. Behavioral Neuroscience. 120 (5): 1093–102. doi:10.1037/0735-7044.120.5.1093. PMID 17014260.
  11.  Felszeghy K, Espinosa JM, Scarna H, Bérod A, Rostène W, Pélaprat D (December 2007). “Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference”. Neuropsychopharmacology. 32 (12): 2601–10. doi:10.1038/sj.npp.1301382. PMC 2992550free to read. PMID 17356568.
  12.  Lévesque K, Lamarche C, Rompré PP (October 2008). “Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine”.European Journal of Pharmacology. 594 (1–3): 132–8. doi:10.1016/j.ejphar.2008.07.048. PMID 18706409.

//////////////////////Flow synthesis, Meclinertant, SR48692, Reminertant,  SR 48692, 146362-70-1

COC1=C(C(=CC=C1)OC)C2=CC(=NN2C3=C4C=CC(=CC4=NC=C3)Cl)C(=O)NC5(C6CC7CC(C6)CC5C7)C(=O)O

Continuous Flow Stereoselective Synthesis of (S)-Warfarin


Figure

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

str1

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
E-mail: mapericas@iciq.es
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

Synthesis:

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%.

NMR 

General Data:

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

C19H16O4

CAS Number:
81-81-2
Molecular Weight:
308.33
Structure:
Isomers:
Optical Isomers: S-Warfarin and R-Warfarin
Melting Point /ºC :
161
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. 

 

(R)-(+)-Warfarin

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

R-warfarin 2D

S-Warfarin

S-warfarin 2D

Hemiketal Ring Formation

RR-Warfarin

RR-warfarin 2D

SS-Warfarin

SS-warfarin 2D

RS-Warfarin

RS-warfarin 2D

SR-Warfarin

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

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

menaquinone
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

Review, Continuous Processing


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.

History

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.

Shut-downs

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

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

EXAMPLE…………….

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
Figure

EXAMPLE…………….


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
STR1
STR1
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);
STR1
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;
STR1
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.
Angewandte Chemie International Edition
( Angew. Chem., Int. Ed. 2015,54, 4945−4948).

Volume 54, Issue 16April 13, 2015 Pages 4945–4948

A Concise Flow Synthesis of Efavirenz

  • DOI: 10.1002/anie.201411728
SUPP INFO
STR1
STR1

 NEXT EXAMPLE…………….

 

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

NEXT EXAMPLE…………….

 

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.

https://www.vapourtec.com/flow-chemistry-resource-centre/publications-citing-vapourtec/continuous-flow-processing-of-organometallic-reagents-using-an-advanced-peristaltic-pumping-system-and-the-telescoped-flow-synthesis-of-ez-tamoxifen/

NEXT EXAMPLE…………….

 

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.

NEXT EXAMPLE…………….

 

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

NEXT EXAMPLE…………….

 

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. http://www.csiro.au/products/RAFT.html
STR1

Examples………..

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.

figure

Scheme .  Generation of cyclohexaneperoxycarboxylic acid

Examples………..

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

Examples………..

Abstract Image

Continuous Biocatalytic Processes

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

PICS…………..

References

  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.

Flow synthesis of Fluoxetine


[1860-5397-11-134-i8]

Scheme 1: Flow synthesis of fluoxetine (46).

PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry,  Marcus Baumann and Ian R. Baxendale, Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134

One of the early published examples of industry-based research on multi-step flow synthesis of a pharmaceutical was reported in 2011 by scientists from Eli Lilly/UK and detailed the synthesis of fluoxetine 46, the API of Prozac[1]. In this account each step was performed and optimised individually in flow, with analysis and purification being accomplished off-line. The synthesis commences with the reduction of the advanced intermediate ketone 47 using a solution of pre-chilled borane–THF complex (48) to yield alcohol 49 (Scheme 1).

Conversion of the pendant chloride into iodide 51 was attempted via Finckelstein conditions, however, even when utilising phase-transfer conditions in order to maintain a homogeneous flow regime the outcome was not satisfactory giving only low conversions. Alternatively direct amination of chloride 49 utilising high temperature flow conditions (140 °C) allowed the direct preparation of amine 50 in excellent yield.

Flow processing using a short residence time (10 min) at the elevated temperature allowed for a good throughput; in addition, the handling of the volatile methylamine within the confines of the flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up.

The final arylation of 50 was intended to be performed as a SNAr reaction, however, insufficient deprotonation of the alcohol 50 under flow conditions (NaHMDS or BEMP instead of using a suspension of NaH as used in batch) required a modification to the planned approach. To this end a Mitsunobu protocol based on the orchestrated mixing of four reagent streams (50, 54 and reagents 52 and 53) was developed and successfully applied to deliver fluoxetine (46) in high yield.

Overall, this study is a good example detailing the intricacies faced when translating an initial batch synthesis into a sequence of flow steps for which several adaptations regarding choice of reagents and reaction conditions are mandatory in order to succeed.

Marcus

Dr Marcus Baumann
Postdoc

Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.

Prof. Ian R. Baxendale

Personal web page

Professor in the Department of Chemistry
Telephone: +44 (0) 191 33 42185

(email at i.r.baxendale@durham.ac.uk)

Research Interests

My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.

My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.

For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/

 

  1. Ahmed-Omer, B.; Sanderson, A. J. Org. Biomol. Chem. 2011, 9, 3854–3862. doi:10.1039/C0OB00906G
    Paper

    Preparation of fluoxetine by multiple flow processing steps

    *Corresponding authors
    aEli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK
    Org. Biomol. Chem., 2011,9, 3854-3862

    DOI: 10.1039/C0OB00906G

    http://pubs.rsc.org/en/Content/ArticleLanding/2011/OB/c0ob00906g#!divAbstract

Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.

Graphical abstract: Preparation of fluoxetine by multiple flow processing steps

1 The general method set-up of flow process used for the synthesis of (±)- fluoxetine.

Scheme 1 Synthesis of (±)-fluoxetine in flow: (i) BH3·THF, r.t., 5 min (77%); (ii) NaI, toluene: water, 100 °C, 20 min (43%); (iii); MeNH2 (aq), …

//////////Flow synthesis, fluoxetine

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

Figure
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

Figure
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.

SEE MORE IN THE PUBLICATION…………..

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

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Multistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4- carbonitrilesultistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4- carbonitriles


Using the Uniqsis FlowSyn flow chemistry system researchers from the UCB Biopharma. Belgium have developed a flow synthesis of 2-substituted 1,2,3-triazoles that demonstrates improvements over the conventional batch route.

The route involves the diazotisation of anilines and condensation with malononitrile followed by the nucleophilic addition of ammonia or an alkylamine and finally a novel copper catalysed cyclisation. The intermediate azide was generated and consumed in situ which enabled safe scale up under the flow-through conditions employed.

DOI: 10.1002/chem.201402074

Multistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles

Authors, Dr. Jérôme Jacq, Dr. Patrick Pasau

Corresponding author

  1. UCB Biopharma, Avenue de l’Industrie, 1420 Braine l’Alleud (Belgium)
  • UCB Biopharma, Avenue de l’Industrie, 1420 Braine l’Alleud (Belgium)===

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.http://onlinelibrary.wiley.com/wol1/doi/10.1002/chem.201402074/full

http://onlinelibrary.wiley.com/store/10.1002/chem.201402074/asset/supinfo/chem_201402074_sm_miscellaneous_information.pdf?v=1&s=77c885224607254b0d594d6cd190e655dd4ac7ee

NMR2002

1H/13c NMR OF 1a

NMR1000

NMR1001

 

NMR1004

NMR1005

 

NMR1006

 

NMR1007

UCB Biopharma,  Belgium

 

 

 

Uniqsis FlowSyn

 

Uniqsis Ltd
29 Station Road
Shepreth
Cambridgeshire
SG8 6GB
UK
Telephone
+44 (0)845 864 7747
Email
info@uniqsis.com

 

Map of cambridgeshire

Halifax survey names South Cambridgeshire as best place to live in rural Britain

///////////FLOW SYNTHESIS, UCB Biopharma, Belgium, Uniqsis FlowSyn

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 hornc@corning.com, Carine Cerato-Noyerie

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

hornc@corning.com

http://www.akademiai.com/content/622t676074227362/?p=a966d2661bb04f91919c965b3dbff07c&pi=1

Abstract

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

Important Industrial Procedures Revisited in Flow: Very Efficient Oxidation and N-Alkylation Reactions with High Atom-Economy


http://www.akademiai.com/content/u87p126856085276/?p=2f48c96a10a64882aeb5c47c657a10b7&pi=4

Journal Journal of Flow Chemistry
Publisher Akadémiai Kiadó
ISSN 2062-249X (Print)
2063-0212 (Online)
Subject Flow Chemistry
Issue Volume 3, Number 2/June 2013
Pages 51-58
DOI 10.1556/JFC-D-12-00025
Authors
Gellért Sipos1, Viktor Gyollai1, Tamás Sipőcz1, György Dormán1, László Kocsis1 Email for laszlo.kocsis@thalesnano.com, Richard V. Jones1, Ferenc Darvas1

1ThalesNano Zahony u. 7 1031 Budapest Hungary

László Kocsis holds a Masters degree in Bioorganic Chemistry from the Eötvös Lóránd University in Budapest, Hungary (2001) and a PhD in Organic Chemistry from the Eötvös Lóránd University in Budapest, Hungary (2008). In 2004 he began working as a research chemist at the Reanal Finechemical Company in Budapest, Hungary. He became the Head of the R&D laboratory in 2007 and a manager of production in 2008. In 2011 he joined ThalesNano Inc. as Head of Chemistry. He has experience in organic chemistry, with emphasis on sythesis of amino acid derivatives and peptides, focusing mainly on the following subjects: structure – relationship studies in opiod peptides, methodological studies in the internal solubilization of the sekf-aggregating peptides, industrial scale sythesis of protected amino acid derivatives, and peptides, heterogeneous catalysis, reactions under continuous flow conditions. He is the co-author of 10 pulications and a member of the European Peptide Society.

Abstract

The atom economy concept is one of the earliest recognition for green and sustainable aspects of organic synthesis. Over the years, novel technologies emerged that made this important feature of reactions into practice. Continuous-flow devices increased the efficiency of the chemical transformations with novel process windows (high T, high p and heterogeneous packed catalysts etc.) and increased safety which turned the attention to reexamine old, industrial processes. Oxidation can be performed under flow catalytic conditions with molecular oxygen; alcohols can be oxidized to carbonyl compounds with high atom economy (AE = 87 %). Using O2 and 1 % Au/TiO2, alcohol oxidation in flow was achieved with complete conversion and >90 % yield. N-alkylation is another good example for achieving high atom economy. Under flow catalytic conditions (Raney Ni), amines were successfully reacted with alcohols directly (AE = 91 %) with >90 % conversion and selectivity. In both examples, the effective residence time was less than 1 min. These two examples demonstrate the significant contribution of flow technology to the realization of key principles in green and sustainable chemistry.

ThalesNano Nanotechnology Inc, GraphisoftPark. Záhony u. 7. H-1031 Budapest HUNGARY

A Method to Identify Best Available Technologies (BAT) for Hydrogenation Reactors in the Pharmaceutical Industry


J. Flow Chem. 2012, 2(3), 77–82

http://www.akademiai.com/content/8652651g3378x686/?p=ab7c1bc4cd7740e1855623297649f542&pi=3

http://www.akademiai.com/content/8652651g3378x686/fulltext.pdf

Journal of Flow Chemistry
Publisher Akadémiai Kiadó
ISSN 2062-249X (Print)
2063-0212 (Online)
Subject Flow Chemistry
Issue Volume 2, Number 3/September 2012
Pages 77-82
DOI 10.1556/JFC-D-12-00014
Authors
Tuong Doan1, Petr Stavárek1, Claude Bellefon1 Email for claude.debellefon@lgpc.cpe.fr* Author for correspondence: claude.debellefon@lgpc.cpe.fr

1CNRS, CPE Lyon University of Lyon Villeurbanne France

Abstract

A methodology that may be applied to help in the choice of a continuous reactor is proposed. In this methodology, the chemistry is first described through the use of eight simple criteria (rate, thermicity, deactivation, solubility, conversion, selectivity, viscosity, and catalyst). Then, each reactor type is also analyzed from their capability to answer each of these criteria. A final score is presented using “spider diagrams.” Lower surfaces indicate the best reactor choice. The methodology is exemplified with a model substrate nitrobenzene and a target pharmaceutical intermediate, N-methyl-4-nitrobenzenemethanesulphonamide, and for three different continuous reactors, i.e., stirred tank, fixed bed, and an advanced microstructured reactor. Comparison with the traditional batch reactor is also provided.

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