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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 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 amcrasto@gmail.com, 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......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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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

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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

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

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

 

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///////////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.

 

 

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7 Bis Avenue de Valvins, 77210 Avon, France

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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.

The application of flow microreactors to the preparation of a family of casein kinase I inhibitors


Graphical Abstract

The Application of Flow Microreactors to the Preparation of a Family of Casein Kinase I Inhibitors.
Venturoni, F.; Nikbin, N.; Ley S. V.; Baxendale, I. R.
Org. Biomol. Chem. 2010, 8, 1798-1806.
Link: 10.1039/b925327kpdf icon

In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

aInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
Org. Biomol. Chem., 2010,8, 1798-1806

DOI: 10.1039/B925327K

Flow Chemistry test facility in India


Chemtrix-India Test Facility1

Flow Chemistry test facility in India

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India
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vk@pi-inc.co
0091 9821 3420 22

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info@chemtrix.com
0031 (0)46 70 22 600

EVENTS

Chemtrix at CPhI India
2 – 4 December 2014
Mumbai, India

Booth H47, Hall 5
Pi Process Intensification

Plantrix® MR260 now available for demo’s and trial’s
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To learn more about Industrial Continuous Manufacturing, please click here for a white paper. In addition to providing an overview of commercial examples of industrial scale continuous manufacturing, this article focuses on the key points to consider when embarking on the development of a continuous process.

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Optimisation of Conditions for O-Benzyl and N-Benzyloxycarbonyl Protecting Group Removal using an Automated Flow Hydrogenator


Optimisation of Conditions for O-Benzyl and N-Benzyloxycarbonyl Protecting Group Removal using an Automated Flow Hydrogenator

K.R. Knudsen, J. Holden, S.V. Ley and M. Ladlow, Adv. Syn. Cat. 2007, 349, 535-538.

http://onlinelibrary.wiley.com/doi/10.1002/adsc.200600558/abstract

A versatile, fully automated flow hydrogenator has been developed that is able to perform sequential flow optimisation experiments, flow library hydrogenation, or iterative scale-up hydrogenation. The behaviour of a palladium catalyst in effecting removal of O-benzyl and N-benzyloxycarbonyl protecting groups has been investigated. Significant observations relating to maintaining optimal throughput are reported. A small library of peptidic derivatives has been deprotected in high yield and purity.

 

System configuration:
The system used was configured from a Gilson liquid handler (233XL), driven with a 10 mL
syringe pump (402). The syringe pump was connected to the sampling needle via a 2-way 6
position switching valve. This single channel liquid handler was used to perform both substrate
manipulation and fraction collection. The liquid handler was connected via a 2-way 6 position
injection valve to a Thales H-CubeTM flow hydrogenator driven with a KnauerTM A120 high
pressure pump. The collection vials were housed in specially designed gas tight blocks (2 x 7)
which were fitted with PTFA seals to enable penetration by the liquid handler needle, and
continuously purged with nitrogen in order to dilute and vent excess hydrogen safely. The
hardware was controlled using a single graphic user interface (HydroMateTM, Figure 2) which
utilised either RS232 or GSIOC connectivity to interface with the Thales and Gilson devices
respectively. Throughout 30 mm, 4 mm id 10% Pd/C catalyst cartridges (CatCartTM) were used
in conjunction with a 5 mL sample injection loop, although larger cartridges are also available.

 

The control software exploits software ‘wizards’ to assist the user in compiling a sequence of
optimisation experiments, or alternatively permits the implementation of a series of repetitive
experiments for either: (i) catalyst evaluation, (ii) reaction optimisation, (iii) compound library
synthesis, or (iv) as part of an automated, unattended scale up campaign (Figure 1). Experiments
may be devised with variations in scale, temperature, flow rate, and pressure in addition to
periodicity of fraction collection.
Analysis: RP-HPLC was run on a Hewlett Packard 1050 instrument. Column: Supelcosilä
ABZ+
PLUS column, 3.3 cm, 4.6 mm f, 3 mm. Eluent: A: water, 0.1% TFA, B: acetonitrile 95%,
water 5%, TFA 0.05%. Gradient: 10 to 95% B in A (1 mL min-1
) over 8 min. Detection: UV
(diode array detector).

A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis


 

A Microcapillary Flow Disc (MFD) Reactor for Organic Synthesis,

C.H. Hornung, M.R. Mackley, I.R. Baxendale and S.V. Ley and, Org. Proc. Res. Dev., 2007, 11, 399-405.

http://pubs.acs.org/doi/abs/10.1021/op700015f

This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80−250 μm. MCFs were wound into spirals and heat treated to form solid discs, which were then capable of carrying out continuous flow reactions at elevated temperatures and pressures and with a controlled residence time. Three reaction schemes were conducted in the system, namely the synthesis of oxazoles, the formation of an allyl-ether, and a Diels−Alder reaction. Reaction scales of up to four kilograms per day could be achieved. The potential benefits of the MFD technology are compared against those of other reactor geometries including both conventional lab-scale and other microscale devices.

 

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