Maurizio Benaglia

University of Milan, Milano · Department of Chemistry

Maurizio Benaglia

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

*E-mail: maurizio.benaglia@unimi.it., 

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  University of Milan

  Department of Chemistry

  Milano, Italy

Maurizio Benaglia

MAURIZIO BENAGLIA was born in Bergamo in 1966.
In 1991 he obtained his Laurea in chemistry, at the University of Milan, Italy, working on the stereoselective 1,3 dipolar cycloadditions of nitrones to chiral allyl ethers.
In 1994 he completed his doctoral studies on the stereoselective synthesis of β-lactams through condensation of imines to titanium, tin and β-boron enolates of pyridylthioesters, under the supervision of prof. Mauro Cinquini, at the University of Milan.
In 1995, he was the recipient of a N.A.T.O./CNR postdoctoral fellowship and joined the group of prof. Jay. S. Siegel, at the Chemistry and Biochemistry Department of UCSD, University of California, San Diego where he worked for two years on the stereocontrolled synthesis of supramolecular structures, like double helicates, racks, and grids.
In 1997 he moved back to Milan, where he worked as postdoctoral fellow at the Department of Organic and Industrial Chemistry, University of Milan, developing the stereoselective synthesis of polymer supported small organic molecules.
In 2000 he became assistant professor at Department of Organic and Industrial Chemistry, University of Milan and in 2006 associate professor at the University of Milan.
In 2001 he won the "Giacomo Ciamician" Medal of the Italian Chemical Society.
He has been awarded by Elsevier as author of one 50 most cited papers in 2003-2006 years, author of one of the most 50 cited papers in 2006-9 years, and author of one of the 20 most cited papers in Organic Letters in 2006-2009 years (highlighted in Synform 2007).
In 2014 he has won the award “Innovation in research”, given by National Consortium of Italian University C.I.N.M.P.I.S.
In 2015 he was promoted to full professor at the Department of Chemistry, University of Milano, Italy.
He has been invited plenary speaker at al 9th Meeting on Stereochemistry (Praga, 2001), 5th Spanish Italian Symposium on Organic Chemistry (Santiago de Compostela, Spain, 2004), “Organocatalysis Symposium” held by Ernst Schering Foundation (Berlin, Germany, 2007), German-Italian-Austrian-French Symposium (Goslar, Germany, 2011)..
Participant to the COST ORCA action (Organocatalysis), he is member of the editorial board of “Recoverable catalysis” (Versita) and “Recent Patents in Catalysis” (Bentham). He has presented several posters, oral communications, key note and invited lectures at national and international scientific congresses. He is author of more than 170 publications on scientific international journals, including four patents, ten review articles and nine book chapters (h index 38). He has been editor of the Wiley book Recoverable and recyclable catalysts (2009).
He is the actual director of the "INTERNATIONAL SUMMER SCHOOL ON ORGANIC SYNTHESIS "A. CORBELLA" – ISOS. [Link]

Teaching activity

Organic chemistry lab class (base)
Catalytic methods in organic synthesis (advanced)
Advanced organic chemistry for Graduate School in Chemistry of University of Milano, Italy

Funding

Grant by Cariplo Foundation: "Biodegradable polymers with controlled macromolecular architecture as new polyfunctional agents for 19F MR imaging" 2011-2013 budget: 410.000 euro
Grant by Cariplo Foundation: "Multifunctional hybrid materials as novel chiral recyclable catalysts for one-pot, multi-step synthesis of structurally complex molecules" 2011-2014 budget: 350.000 euro
Grant by MIUR - FIRB "Futuro in Ricerca 2010 Multifunctional hybrid materials for the development of sustainable catalytic processes" 2012-2016 budget: 326.200 euro (with Alessandra Puglisi)
Funding by:
Laboratori Alchemica: budget 20.000 (2015)
Wiz Chemicals: budget 20.000 (2014-2015)
Zach Systems: budget 80.000 euro (2012-2015)
ZaCh Systems: budget 40.000 euro (2011-2012)
Versalis (ENI polimeri): budget 20.000 euro (2012)
Ferrania Technologies: budget 60.000 euro (2010-2012)
Past collaboration (2003-2009) with Oxon, Sipcam and Dani Instruments.

Contact: maurizio.benaglia@unimi.it

 

Recent publications:

S. Rossi,M. Benaglia, A. Genoni, F. Cozzi, T. Benincori:
Organocatalytic stereoselective direct aldol reaction of trifluoroethyl thioesters
Adv. Synth. Catal., Vol. 353, (2011), pp.848-854.

S. Guizzetti,M. Benaglia, M. Bonsignore, L. Raimondi:
Triclorosilane mediated stereoselective synthesis of  b-amino esters and their conversion to highly enantiomerically enriched  b-lactams.
Org. Biomol. Chem.,Vol. 9, (2011), pp. 739-743.

M. Benaglia, F. Cozzi, A. Mazzanti, M. Mancinelli:
The Intramolecular Interaction of Thiophene and Furan with Aromatic and Fluoroaromatic Systems in some[3,3]meta(heterocyclo)paracyclophanes: a Combined Computational and NMR study.
Chem. Eur. J.,Vol. 16, (2010), pp. 7456-7468.

S. Guizzetti,M. Benaglia,  S. Rossi:
Highly stereoselective metal-free catalytic reduction of imines: an easy entry to enantiomerically pure amines and natural and unnatural a-amino esters.
Org. Lett., Vol.11, (2009), pp. 2928-2931.

A. Puglisi, R. Annunziata,  M. Benaglia, F. Cozzi, A. Gervasini, V. Bertacche, M. C. Sala:
Hybrid inorganic-organic materials carrying tertiary amine and thiourea residues tethered on mesoporous silica nanoparticles: synthesis, characterization and cooperative catalysis.
Adv. Synth. Catal., 2009, 351, 219-229.

V. Simonini, M. Benaglia,T. Benincori:
Novel chiral biheteroaromatic diphosphine oxides for Lewis base activation of Lewis acids in enantioselective allylation and epoxide opening
Adv. Synth. Catal., Vol. 350,(2008), pp. 561-564.

M. Bandini,  M. Benaglia, R. Sinfisi, S. Tommasi, A. Umani-Ronchi:
Recoverable PEG-supported copper catalyst for highly stereocontrolled nitroaldol condensation.
Org. Lett., Vol. 9, (2007),pp. 2151-2153.

S. Guizzetti,M. Benaglia,  L. Raimondi, G. Celentano:
Enantioselective direct aldol reaction “on water” promoted by chiral organic catalyst.
Org. Lett., Vol. 9, (2007),pp. 1247-1250.

M. Bandini, M. Benaglia, T. Quinto, S. Tommasi, A. Umani-Ronchi:
New Recoverable Poly(ethylen glycol)-supported C₁–Diamino-oligothiopheneLigands    for Pd-Promoted AAA Reactions
Adv. Synth. Catal.,  Vol. 348, (2006), pp. 1521-1527.

L. Pignataro, M. Benaglia, R. Annunziata, F. Cozzi, M. Cinquini:
Structurally simple pyridine N-oxides as efficient organocatalysts for the enantioselective allylation of aromatic aldehydes.
J. Org. Chem., Vol. 71, (2006),pp. 1458-1463.

Profilo	Professore Ordinario
Settore	Settore Chim/06 - Chimica Organica
Settore concorsuale	03/C1 - Chimica Organica
Struttura di assegnazione	Dipartimento di Chimica Sito della struttura

Sede lavorativa	Via Golgi, 19 20133 - Milano (MI)
Telefono Ufficio	02503 14171
E Mail	maurizio.benaglia@unimi.it
Fax	02 503.14159

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

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

1  Diphenhydramine Hydrochloride

Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride

Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.

In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.

The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Scheme 2. Continuous Flow Synthesis of Olanzapine

Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.

In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd₂dba₃ as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H₂O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et₃SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.

The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)₄ as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.

SEE MORE IN THE PUBLICATION…………..

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Riccardo Porta, Maurizio Benaglia^*, and Alessandra Puglisi^*

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

*E-mail: maurizio.benaglia@unimi.it., *E-mail: alessandra.puglisi@unimi.it.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00325

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.

 

COST meeting Action ORCA, Organocatalysis (Palermo, Italy, 2014)
International Conference "Catalysis in Organic Synthesis" (Moscow, Russia, 2012)	COST meeting Action ORCA, Organocatalysis (Rome, Italy, 2012)	COST meeting Action ORCA, Organocatalysis (Rome, Italy, 2012)

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

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