Development and Scale-Up of a Continuous Reaction for Production of an Active Pharmaceutical Ingredient Intermediate

FLOW CHEMISTRY, flow synthesis Comments Off

Aug 242018

Flow reactor equipment that was used in the piloting of the aldol flow chemistry. (a) The tube-in-shell heat exchangers were used to control stream temperature upstream and downstream of the (b) Y-mixer. Valves and ports on Y-mixer enabled flushing of lines and incorporation of inline thermocouples.

Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical drug substance research. Developing these processes for robust commercialization and identifying the scale-up parameters remains a challenge. An aldol reaction in the formation of an active pharmaceutical ingredient intermediate was developed in flow at the milliliter scale. Research focused on identifying conditions that led to robust and stable operating conditions. Desired reaction performance was achieved in various mixers across reactor scales by identifying conditions that led to similar flow regimes. Conditions from the lab were transferred to the pilot plant to successfully process ∼200 kg of the starting material.

Development and Scale-Up of a Continuous Reaction for Production of an Active Pharmaceutical Ingredient Intermediate

Jonathan P. McMullen*

, Christopher H. Marton, Benjamin D. Sherry, Glenn Spencer, Joseph Kukura, and Natalie S. Eyke

Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00192

*E-mail: jonathan.mcmullen@merck.com.

Conclusions

A flow chemistry process for sustainable operations was developed by utilizing THF as a cosolvent to improve the solubility of the reagent degradants. Process robustness was further established by understanding the impact of mixing, residence time, and solvent composition on reaction performance. Identifying a suitable flow regime via the Reynolds number was identified as the scaling parameter for this flow reaction and used to scale the flow reaction from 20 mL/min in the lab to 1.6 L/min in the production environment. A modular flow reactor skid was fabricated for facile integration of flow chemistry components with existing batch equipment and was used to process 200 kg of starting material.

READ AT……….https://pubs.acs.org/doi/10.1021/acs.oprd.8b00192

///////////////Development, Scale-Up, Continuous Reaction, Production, Active Pharmaceutical Ingredient, Intermediate, flow chemistry, mixing sensitive reaction, scale-up

Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry

FLOW CHEMISTRY, flow synthesis Comments Off

Jul 172018

We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have designed, 3D-printed, and characterized a stainless steel static mixer. This approach enabled the evaluation of different configurations and ensured efficient scale-up across development and commercial facilities that should allow for enhanced portability of mixing-sensitive processes.

Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry

François Lévesque*

, Nicholas J. Rogus*, Glenn Spencer, Plamen Grigorov, Jonathan P. McMullen, David A. Thaisrivongs

, Ian W. Davies^†, and John R. Naber

Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00063

*E-mail: francois.levesque@merck.com., *E-mail: nicholas_rogus@merck.com.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00063

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00063/suppl_file/op8b00063_si_001.pdf

Associate Principal Scientist at Merck

François Lévesque

//////////////FLOW CHEMISTRY,

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Uncategorized Comments Off

Dec 222016

Abstract Image

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Joseph D’Attoma^†, Titi Camara^‡, Pierre Louis Brun^‡, Yves Robin^‡, Stéphane Bostyn^*^§, Frédéric Buron^*^†

, and Sylvain Routier^*^†

^† Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067 CEDEX 2 Orléans, France

^‡ ISOCHEM, 4 Rue Marc Sangnier, BP 16729, 45300 Pithiviers, France

^§ Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, Avenue de la Recherche Scientifique, 45071 CEDEX 2 Orléans, France

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00318, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00318

*E-mail: frederic.buron@univ-orleans.fr., *E-mail: sylvain.routier@univ-orleans.fr., *E-mail: stephane.bostyn@univ-orleans.fr.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

2,5-Dichloro-1,3-benzoxazole (33)

The reaction was carried out as described in general procedure B using 2-Amino-5-chlorobenzoxazole (221 mg, 1.31 mmol). After purification with silica flash chromatography (EP 100%), the product was isolated as a yellow oil (62 mg, 25%).

CAS number 3621-81-6.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

¹³C NMR (101 MHz, Chloroform-d) δ 152.27 (C), 150.12 (C), 142.06 (C), 130.79 (C), 125.85 (CH), 119.78 (CH), 111.16 (CH).

HRMS [M + H]+ (EI) calcd for C₇H₄Cl₂NO: 187.9664, found: 187.9663.

1H NMR PREDICT

13 C NMR PREDICT

/////////////

Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles

FLOW CHEMISTRY, flow synthesis Comments Off

Oct 232016

Compound 3aa was obtained as pale yellow oil (163 mg, 92% yield).MS (ESI): mass calcd. for C12H16O3, 208.1099; m/z found, 209.1102 [M+H] + .

1H NMR (CHLOROFORM-d, 400MHz): δ = 7.45 (d, J=7.7 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.21-7.27 (m, 1H), 4.37 (s, 1H), 4.00-4.18 (m, 2H), 2.97 (d, J=15.9 Hz, 1H), 2.79 (d, J=15.9 Hz, 1H), 1.55 (s, 3H), 1.08-1.18 ppm (m, 3H).

13C NMR (CHLOROFORM-d, 101MHz): δ = 173.1, 147.3, 128.6, 127.3, 124.9, 73.2, 61.4, 46.9, 31.1, 14.4 ppm

The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a novel green activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into -bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems in a one pot procedure.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02619B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles.

Jesus Alcazar, Antonio de la Hoz, Angel Diaz, Lena Huck and Mateo Berton

Green Chem., 2016, Accepted Manuscript

DOI: 10.1039/C6GC02619B

////////////Reformatsky, Blaise Reactions , Flow chemistry, Drug Discovery. One Pot, Diversity Oriented Synthesis, Valuable Intermediates, Heterocycles.

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

PROCESS, SYNTHESIS, Uncategorized Comments Off

Oct 202016

Evacetrapib

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

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

Scott A. May^*, Martin D. Johnson^*, Jonas Y. Buser, Alison N. Campbell, Scott A. Frank, Brian D. Haeberle‡, Philip C. Hoffman, Gordon R. Lambertus, Adam D. McFarland, Eric D. Moher, and Timothy D. White ,

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

D. Declan Hurley^*, Aoife P. Corrigan, Olivia Gowran, Niall G. Kerrigan, Marie G. Kissane, Regina R. Lynch, Paul Sheehan, and Richard D. Spencer ,

Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland

Shon R. Pulley§ and James R. Stout

D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00148

Publication Date (Web): October 19, 2016

*E-mail (Scott A. May): may_scott_a@lilly.com., *E-mail: (Martin D. Johnson): johnson_martin_d@lilly.com., *E-mail: (Declan D. Hurley):hurley_declan_d@lilly.com.

link http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00148

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

/////////continuous manufacturing, deviation boundaries, Evacetrapib, flow chemistry, GMP, homogeneous catalysis, hydrogen, hydrogenation, iridium, lot genealogy, LY2484595, online HPLC, process analytical technologies, reductive amination, start up and shutdown transitions, state of control, steady state, [Ir(COD)Cl]₂

Diphenhydramine Hydrochloride, Use of Flow Synthesis

flow synthesis Comments Off

Sep 062016

Diphenhydramine Hydrochloride

REGULAR SYNTHESIS

FLOW SYNTHESIS

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 3 minimizing 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 2 and 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.

REF

Snead, D. R.; Jamison, T. F. Chem. Sci. 2013, 4, 2822, DOI: 10.1039/c3sc50859e

End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts

David R. Snead^a and Timothy F. Jamison*^a

*Corresponding authors

^aMassachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Ave., Cambridge, USA
E-mail: tfj@mit.edu
Tel: +1 617 253-2135

Chem. Sci., 2013,4, 2822-2827

DOI: 10.1039/C3SC50859E, http://pubs.rsc.org/en/content/articlelanding/2013/sc/c3sc50859e#!divAbstract

A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1:1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) production in this manner. Six of the twelve principles of green chemistry as defined by the American Chemical Society are achieved, most prominently waste minimization and atom economy.

Graphical abstract: End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts

A CLIP

In 2013 the Jamison group reported the flow synthesis of the important H₁-antagonist diphenhydramine·HCl (92) showcasing the potential of modern flow chemistry to adhere to green chemistry principles (minimal use of organic solvents, atom economy etc.) . The synthetic strategy relied on reacting chlorodiphenylmethane (93) with an excess of dimethylaminoethanol (94) via a nucleophilic substitution reaction (Scheme ).

Scheme : Flow synthesis of diphenhydramine^.HCl (92).

As both starting materials are liquid at ambient temperature the use of a solvent could be avoided allowing direct generation of the hydrochloride salt of 92 in a high temperature reactor (175 °C) with a residence time of 16 min. Conveniently at the same reaction temperature the product was produced as a molten paste (m.p. 168 °C) which enabled the continued processing of the crude product circumventing any clogging of the reactor by premature crystallisation. Analysis of the crude extrude product revealed the presence of minor impurities (<10%) even when stoichiometric amounts of 94 were used, consequently an in-line extraction process was developed. Additional streams of aqueous sodium hydroxide (3 M, preheated) and hexane were combined with the crude reaction product followed by passage through a membrane separator. The hexane layer was subsequently collected and treated with hydrochloric acid (5 M in IPA) leading to the precipitation of diphenhydramine hydrochloride (92) in high yield (~90%) and purity (~95%). Furthermore, options to further reduce waste generated during the purification sequence are presented by combining hot IPA with the crude flow stream leading to the isolation of the target compound (92·HCl) by direct crystallisation in the collection vessel (yield 71–84%, purity ~93%, productivity 2.42 g/h).

David Snead

dsnead at mit dot edu

Ph.D.	The University of Florida, 2010 with Prof. Sukwon Hong
B.S.	The University of North Carolina at Chapel Hill, 2005 with Prof. Joseph DeSimone

Image result for Timothy F. Jamison

Timothy F. Jamison

Professor of Chemistry
Massachusetts Institute of Technology
Department of Chemistry
77 Massachusetts Ave., Bldg 18-590
Cambridge, MA 02139

Phone: (617) 253-2135
Fax: (617) 324-0253
Email: tfj at mit dot edu

Curriculum Vitae

Tim Jamison was born in San Jose, CA and grew up in neighboring Los Gatos, CA. He received his undergraduate education at the University of California, Berkeley. A six-month research assistantship at ICI Americas in Richmond, CA under the mentorship of Dr. William G. Haag was his first experience in chemistry research. Upon returning to Berkeley, he joined the laboratory of Prof. Henry Rapoport and conducted undergraduate research in his group for nearly three years, the majority of which was under the tutelage of William D. Lubell (now at the University of Montreal). A Fulbright Scholarship supported ten months of research in Prof. Steven A. Benner’s laboratories at the ETH in Zürich, Switzerland, and thereafter he undertook his PhD studies at Harvard University with Prof. Stuart L. Schreiber. He then moved to the laboratory of Prof. Eric N. Jacobsen at Harvard University, where he was a Damon Runyon-Walter Winchell postdoctoral fellow. In July 1999, he began his independent career at MIT, where his research program focuses on the development of new methods of organic synthesis and their implementation in the total synthesis of natural products.

Image result for Diphenhydramine Hydrochloride

MASS

13C NMR

RAMAN

//////////////////////Diphenhydramine Hydrochloride, Flow Synthesis, FLOW CHEMISTRY

Asian International Continuous Flow Chemistry Summit/Chemtrix BV at CPhI-China 2016

Uncategorized Comments Off

Jun 042016

Asian International Continuous Flow Chemistry Summit at CPhI-China 2016

weblink…….http://www.chemtrix.com/news/65/Asian-International-Continuous-Flow-Chemistry-Summit

CPhI – China on 22nd June 2016

Asian International Continuous Flow Chemistry Summit at CPhI-China 2016

Asian International Continuous Flow Chemistry Summit

The Asian International Continuous Flow Chemistry Summit is this year held during CPhI China 2016, in Shanghai. Focussing on industrial applications, this summit provides usefull in-depth insights and perspectives for companies looking to apply continuous flow chemistry on an industrial scale. The ICFCS provides the opportunity to engage with experienced industrial flow chemistry users through interactive discussion sessions. With international speakers from DSM, Cipla, Zhejiang Technology University and more, join us to hear about;

Industrial case studies and drivers
Methods to transfer from batch to flow
Useful insights from experienced flow chemistry users
Robust, chemical resistant industrial flow reactors

The summit is held in the Shanghai Expo Center (SNIEC), on Wednesday 22nd June, from 13:30 – 16:30.

see…….weblink…….http://www.chemtrix.com/news/65/Asian-International-Continuous-Flow-Chemistry-Summit

Click here for more information. Click here for directions to the summit.

If you would like to register please send this registration form back to info@chemtrix.com.

ORGANISERS

Dr Charlotte Wiles , CHEMTRIX

UK &THE NETHERLANDS,UNIV OF HULL

SPEAKERS

Vijay Kirpalani

Mr Vijay Kirpalani

President
Flow Chemistry Society – India Chapter, INDIA

CEO, PI PROCESS INTENSIFICATION EXPERTS INDIA

UNIT HEAD , API R&D CIPLA INDIA &

Flow Chemistry Society – India Chapter, INDIA

TU EINDHOWEN

Chemtrix BV, a pioneer in the field of continuous flow reactors, further strengthens ties with the Chinese chemical market. China is a very important market for Chemtrix and the Chinese Government actively supporting programs to make the chemical industry more sustainable and safe, means interest in flow reactors is bigger than ever.

To actively support our Chinese clients with this transition, it is important to have facilities in China where Customers can test their chemistry using continuous flow reactors. ‘Our test facility at Zhejiang University of Technology & Shanghai Advanced Research Institute, Chinese Academy of Sciences enables us to show our flow reactors to clients and more importantly, it enables us to test the Customers’ chemistry and develop a program for implementation with the Customer’, comments Imee Zhong, commercial manager at Shenzhen E-Zheng Technology Co. Ltd.(www.e-zheng.com).

E-Zheng is Chemtrix’ local representative in China and their flow chemists have tested 100’s of reactions over the past years for industrial clients. ‘Working with Chemtrix we have built up a strong local experience that we bring to each new Customer case’, states Zhong.

‘Being able to test chemistry for Customers is one thing, but as a leading flow reactor company we also take responsibility to educate students using this technology’, comments Stan Hoeijmakers, Marketing Manager at Chemtrix. ‘This secures the future of the technology as students will enter industrial companies with the knowledge needed to keep the transformation going’. To do so, Chemtrix is building strong relationships with Chinese Universities such as Zhejiang University of Technology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Sichuan University, Xuzhou College, Beijing University and Nanjing Tech University, to name a few.

‘This combination of efforts in teaching & research at Universities and feasibility studies for industrial companies provides a strong base for further developing change in the Chinese chemical market’, concludes Hoeijmakers.

////////////Asian International, Continuous , Flow Chemistry, Chemtrix BV, CPhI-China 2016

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

flow synthesis Comments Off

Jun 022016

MESSAGE FROM VIJAY KIRPALANI

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

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

with speakers from India, UK, Netherlands and Hungary.

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

The Fees are Rs. 5,000 for Industry Delegates and Rs. 2,500 for Academic Delegates (+15% Service Tax) : contact : vk@pi-inc.co or msingh@cipla.com

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

Vijay Kirpalani

Best regards

Vijay Kirpalani
President
Flow Chemistry Society – India Chapter
email : vk@pi-inc.co
Tel: +91-9321342022 // +91-9821342022

ABOUT

IICT, Hyderabad, India

Dr. S. Chandrasekhar,
Director

CSIR-Indian Institute of Chemical Technology (IICT)

Hyderabad, India

SPEAKERS

Vijay Kirpalani

Mr Vijay Kirpalani

President
Flow Chemistry Society – India Chapter, INDIA

Dr Charlotte Wiles , CHEMTRIX

UK &THE NETHERLANDS,UNIV OF HULL

Prof Anil Kumar( IIT-B), INDIA

CIPLA &

Flow Chemistry Society – India Chapter, INDIA

IICT, INDIA

TU EINDHOWEN

GLIMPSE OF HYDERABAD INDIA

OLD MAP

NEW MAP

TAN DOORI CHICKEN IN HYDERABAD

BIRYANI

/////

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

Nanopalladium-catalyzed conjugate reduction of Michael acceptors – application in flow

SYNTHESIS Comments Off

May 212016

Green Chem., 2016, 18,2632-2637
DOI: 10.1039/C5GC02920A, Communication

Anuja Nagendiran, Henrik Sorensen, Magnus J. Johansson, Cheuk-Wai Tai, Jan-E. Backvall
A continuous-flow approach towards the selective nanopalladium-catalyzed hydrogenation of the olefinic bond in various Michael acceptors, which could lead to a greener and more sustainable process, has been developed.

Nanopalladium-catalyzed conjugate reduction of Michael acceptors – application in flow

Communication

Nanopalladium-catalyzed conjugate reduction of Michael acceptors – application in flow

Anuja Nagendiran,^a^b Henrik Sörensen,^b^c Magnus J. Johansson,^b^c Cheuk-Wai Tai^d and Jan-E. Bäckvall*^a^b

*Corresponding authors

^aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
E-mail: jeb@organ.su.se

Berzelii Centre EXSELENT on Porous Materials, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden

AstraZeneca R&D, Innovative Medicines, Cardiovascular and Metabolic Disorders, Medicinal Chemistry, Pepparedsleden 1, SE-431 83 Mölndal, Sweden

Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91, Stockholm, Sweden

Green Chem., 2016,18, 2632-2637

DOI: 10.1039/C5GC02920A

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C5GC02920A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A continuous-flow approach towards the selective nanopalladium-catalyzed hydrogenation of the olefinic bond in various Michael acceptors, which could lead to a greener and more sustainable process, has been developed. The nanopalladium is supported on aminofunctionalized mesocellular foam. Both aromatic and aliphatic substrates, covering a variation of functional groups such as acids, aldehydes, esters, ketones, and nitriles were selectively hydrogenated in high to excellent yields using two different flow-devices (H-Cube® and Vapourtec). The catalyst was able to hydrogenate cinnamaldehyde continuously for 24 h (in total hydrogenating 19 g cinnanmaldehyde using 70 mg of catalyst in the H-cube®) without showing any significant decrease in activity or selectivity. Furthermore, the metal leaching of the catalyst was found to be very low (ppb amounts) in the two flow devices.

////////Nanopalladium-catalyzed, conjugate reduction, Michael acceptors, application, flow chemistry

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

PROCESS, SYNTHESIS Comments Off

Mar 232016

Herein, the first continuous cross-dehydrogenative homocoupling of an unactivated arene using oxygen as sole oxidant is reported. Employing microreactor technology which enables the use of elevated temperatures and pressures leads to a boost of the catalytic reaction. Hence, a major reduction in reaction time is achieved. Due to the significance as precursor for MOFs as well as high-tech and high-value polymers, the study focused on the production of 3,4,3′,4′-tetramethyl-biphenyl.

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

Nico Erdmann, Yuanhai Su, Benjamin Bosmans, Volker Hessel, and Timothy Noël^*

Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00044

Publication Date (Web): March 10, 2016

*E-mail: t.noel@tue.nl.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00044

Supporting Info SEEEEEEEEEEEEE

////Palladium-Catalyzed Aerobic Oxidative Coupling, o-Xylene, Flow, Safe and Scalable Protocol, Cross-Dehydrogenative Coupling

PICS

Cross-dehydrogenative coupling reactions. : The electron is a …

www.nature.com

Cross-dehydrogenative coupling reactions.

Enhancing the usefulness of cross dehydrogenative coupling …

pubs.rsc.org

Cross dehydrogenative coupling (CDC) reactions with different protecting group strategies.

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