AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

 Uncategorized  Comments Off on Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process
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

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

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

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, Har), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, Har), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, Har).
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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

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13 C NMR PREDICT

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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 on Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles
Oct 232016
 

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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

 

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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.

Green Chem., 2016, Accepted Manuscript

DOI: 10.1039/C6GC02619B

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

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

 PROCESS, SYNTHESIS, Uncategorized  Comments Off on Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction
Oct 202016
 
Evacetrapib.svg

Evacetrapib

Abstract Image

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.

Figure

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

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland
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
Copyright © 2016 American Chemical Society
*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.

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.

 

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Diphenhydramine Hydrochloride, Use of Flow Synthesis

 flow synthesis  Comments Off on Diphenhydramine Hydrochloride, Use of Flow Synthesis
Sep 062016
 
Image result for Diphenhydramine hydrochloride
Diphenhydramine Hydrochloride
Image result for Diphenhydramine Hydrochloride
Image result for Diphenhydramine Hydrochloride
REGULAR SYNTHESIS
Figure
FLOW SYNTHESIS
 Image result for 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 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 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.
Image result for Diphenhydramine hydrochloride
REF

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

Image result for 10.1039/c3sc50859e
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 ).

[1860-5397-11-134-i16]
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).

 

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David Snead

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.

 

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IR

 

MASS

13C NMR

RAMAN

 

//////////////////////Diphenhydramine Hydrochloride,  Flow Synthesis, FLOW CHEMISTRY
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Asian International Continuous Flow Chemistry Summit/Chemtrix BV at CPhI-China 2016

 Uncategorized  Comments Off on Asian International Continuous Flow Chemistry Summit/Chemtrix BV at CPhI-China 2016
Jun 042016
 

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Asian International Continuous Flow Chemistry Summit at CPhI-China 2016

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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

Charlotte Wiles

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

 

 

 

 

Manjinder Singh

 

 

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

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

 flow synthesis  Comments Off on Flow Chemistry Symposium & Workshop 16-17 June at IICT, Hyderabad, India
Jun 022016
 

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MESSAGE FROM VIJAY KIRPALANI

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..

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​​

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

 

Charlotte Wiles

Dr Charlotte Wiles , CHEMTRIX

UK &THE NETHERLANDS,UNIV OF HULL

 

Prof. Anil Kumar

Prof Anil Kumar( IIT-B), INDIA

 

Manjinder Singh

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,

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

 SYNTHESIS  Comments Off on Nanopalladium-catalyzed conjugate reduction of Michael acceptors – application in flow
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


*Corresponding authors
aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
E-mail: jeb@organ.su.se
b
Berzelii Centre EXSELENT on Porous Materials, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
c
AstraZeneca R&D, Innovative Medicines, Cardiovascular and Metabolic Disorders, Medicinal Chemistry, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
d
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.

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

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

 PROCESS, SYNTHESIS  Comments Off on Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling
Mar 232016
 

 

Abstract Image

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

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
Copyright © 2016 American Chemical Society
*E-mail: t.noel@tue.nl.

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

 PROCESS, SYNTHESIS  Comments Off on Nanopalladium-catalyzed conjugate reduction of Michael acceptors – application in flow
Mar 102016
 

 

Green Chem., 2016, Advance Article
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.
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
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3 Gottlieb, H. E.; Kotlyar, V; Nudelman, A. J. Org. Chem. 1997, 62, 7512-7515.
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Nanopalladium-catalyzed conjugate reduction of Michael acceptors – application in flow

*Corresponding authors
aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
E-mail: jeb@organ.su.se
bBerzelii Centre EXSELENT on Porous Materials, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
cAstraZeneca R&D, Innovative Medicines, Cardiovascular and Metabolic Disorders, Medicinal Chemistry, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
dDepartment of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91, Stockholm, Sweden
Green Chem., 2016, Advance Article

DOI: 10.1039/C5GC02920A

///////

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Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

 PROCESS, SYNTHESIS  Comments Off on Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products
Jan 052016
 

 

Abstract Image

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

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

 

1  Diphenhydramine Hydrochloride

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

2 Olanzapine

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

SEE MORE IN THE PUBLICATION…………..

 

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

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

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

Riccardo Porta

Riccardo Porta

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

Map of milan italy

 

 

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