Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

FLOW CHEMISTRY, flow synthesis Comments Off

Jan 022017

Abstract Image

Over the last 20 years organic carbamates have found numerous applications in pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, and as protecting groups and intermediates for polyurethane synthesis. Recently, in order to avoid phosgene-based synthesis of carbamates, many environmentally benign and alternative pathways have been investigated. However, few examples of carbamoylation of aniline in continuous-flow apparatus have been reported. In this work, we report a high-yielding, dimethyl carbonate (DMC)-mediated carbamoylation of aniline in a fixed-bed continuously fed reactor employing basic zinc carbonate as catalyst. Several variables of the system have been investigated (i.e. molar ratio of reagents , flow rate, and reaction temperature) to optimize the operating conditions of the system.

Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

Sandra Grego, Fabio Aricò, and Pietro Tundo*

Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University of Venice, Dorsoduro 2137, 30123 Venezia, Italia

Org. Process Res. Dev., 2013, 17 (4), pp 679–683

DOI: 10.1021/op4000048, http://pubs.acs.org/doi/abs/10.1021/op4000048

*Tel.: (+39) 041 234 8642. Fax: (+39) 041 234 8620. E-mail: tundop@unive.it.

PIETRO TUNDO

Profile:

PIETRO R. TUNDO is Professor of Organic Chemistry at Ca’ Foscari University of Venice (Italy).
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).
He is Member of the Bureau of IUPAC.

P: Tundo is author of about 300 scientific publications, 40 patents and many books.
His scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry, heteropolyacids, and finally safe alternatives to harmful chemicals.
He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731). He founded and was Chairman (2004-2016) of the Working Party on “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo coordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia, Italy) sponsored by the EU, UNESCO and NATO.
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).

He is holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731) and author of about 260 scientific publications and 30 patents.

Scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry and finally, heteropolyacids.

He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and presently is Chairman of Working Party of “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

P. Tundo co-ordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia), the latter sponsored by the EU, UNESCO and NATO.

Contact:

Professor of Organic Chemistry
Ca’ Foscari University of Venice
IUPAC Bureau Member
Tel. +39 041 2348642
Mob. +39 349 3486191
E-mail: tundop@unive.it

Phone	041 234 8642 / Lab .: 041 234 8669
E-mail	tundop@unive.it green.chemistry@unive.it – 6th IUPAC Conference on Green Chemistry unescochair@unive.it – TUNDO Pietro
Fax	041 234 8620
Web	www.unive.it/persone/tundop

Pietro Tundo

////////Carbamoylation of Aniline, Dimethyl Carbonate, Continuous-Flow Conditions, flow synthesis

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

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

Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes

FLOW CHEMISTRY, flow synthesis Comments Off

Nov 282016

Homogeneous Enantioselective Catalysis in a Continuous-Flow Microreactor: Highly Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes

Takuo Hayashi†, Satoshi Kikuchi†, Yukako Asano‡, Yoshishige Endo§, and Tohru Yamada*†

^† Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan

^‡ Hitachi Research Laboratory, Hitachi, Ltd., 832-2 Horiguchi, Hitachinaka, Ibaraki 312-0034, Japan

^§ Hitachi Plant Technologies, Ltd., 603 Kandatsu-machi, Tsuchiura, Ibaraki 300-0013, Japan

Org. Process Res. Dev., 2012, 16 (6), pp 1235–1240

DOI: 10.1021/op300061k

*yamada@chem.keio.ac.jp. http://pubs.acs.org/doi/suppl/10.1021/op300061k

Abstract

Highly enantioselective homogeneous catalysis under continuous-flow conditions was established for the cobalt-catalyzed borohydride reduction of tetralone derivatives. A microreactor allowed higher reaction temperature with the residence time of 12 min than the corresponding batch system to maintain enantioselectivity as well as reactivity. The present system was directly applied to gram-scale synthesis to afford the reduced product with 92% ee.

////////////Homogeneous Enantioselective Catalysis, Continuous-Flow Microreactor, Highly Enantioselective Borohydride, Reduction of Ketones Catalyzed, Optically Active Cobalt Complexes

Continuous-Flow Diazotization

FLOW CHEMISTRY, flow synthesis Comments Off

Nov 242016

Characterization Data of Compound 7

Mp: 118–120 °C. MS (M + H⁺): 314.

HRMS (ESI) m/z: Calcd for C₁₆H₁₅N₃NaO₄, (M + Na⁺): 336.0960. Found: 336.0899.

IR (KBr) ν/cm^–1: 3447, 3339, 1717, 1714, 1699, 1594.

¹H NMR (CDCl₃, 400 MHz) δ/ppm: 8.50 (s, 1H, Ar–H), 7.88 (d, J = 8.8 Hz, 1H, Ar–H), 7.76 (d, J = 7.6 Hz, 1H, Ar–H), 7.60 (d, J = 8.0 Hz, 1H, Ar–H), 7.54 (t, J = 7.2 Hz, 1H, Ar–H), 7.41 (t, J = 7.2 Hz, 1H, Ar–H), 6.71 (d, J = 9.2 Hz, 1H, Ar–H), 6.28 (br s, 2H, −NH₂), 3.91 (s, 3H, −CH₃), 3.89 (s, 3H, −CH₃).

¹³C NMR (CDCl₃, 100 MHz) δ/ppm: 168.2, 168.0, 152.9, 151.6, 143.4, 131.7, 131.2, 129.4, 128.8, 128.0, 126.3, 118.9, 117.1, 109.8, 52.3, 51.9.

Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

Zhiqun Yu^†, Hei Dong^†, Xiaoxuan Xie^†, Jiming Liu^‡, and Weike Su^*^†^‡

^† National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China

^‡ Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00238

Publication Date (Web): November 17, 2016

*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00238

Abstract

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

//////////////chlorosulfonylation, continuous-flow, diazotization, parallel side reaction

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.

Scalable Flow Chemistry : A Flexible Tool for the Research, Developments and Production of Pharmaceuticals, Fine & Speciality Chemicals

FLOW CHEMISTRY, flow synthesis Comments Off

Oct 072016

Image result for chemtrix bv

Scalable Flow Chemistry : A Flexible Tool for the Research, Developments and Production of Pharmaceuticals, Fine & Speciality Chemicals
– Dr. Charlotte Wiles, Chief Executive Officer, Chemtrix BV, Netherlands

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A PRESENTATION

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Image result for chemtrix bv CHEMTRIX

///////Scalable Flow Chemistry, A Flexible Tool, Research, Developments, Production, Pharmaceuticals, Fine , Speciality Chemicals, Charlotte Wiles, Chief Executive Officer, Chemtrix BV, Netherlands

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

The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

flow synthesis Comments Off

Aug 132016

A key pharmaceutical intermediate (1) for production of edivoxetine·HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solventcomposition, stoichiometry, and operations temperature were optimized to produce 12 g h⁻¹crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h⁻¹ production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000–6000 L batch reactors.

A continuous flow Barbier reaction was employed for the production of a key pharmaceutical intermediate (1) in the synthesis of edivoxetine·HCl (a highly selective norepinephrine re-uptake inhibitor).

US scientists from Eli Lilly and Company and D&M Continuous Solutions, led by Michael Kopach, report the development of a continuous Barbier reaction which preserves chirality and the product obtained in >99% ee. The team ran the process in a series of continuous stirred tank reactors, where residence time, solvent composition, stoichiometry and operations temperature were optimised to produce 12 g per hour of the ketone precursor to 1 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of 1 could then be achieved from the ketone solution with >99% purity.

This process offers up several significant advantages over a traditional Grignard batch process. This continuous flow method gave greater than 30% reduced process mass intensity and magnesium usage relative to the batch method. Equally, the flow process resulted in >100 x less excess magnesium to quench and >100 x less diisobutylaluminum hydride to initiate giving significant safety benefits. The authors expect that the maximum long-term scale of the process is 50 L which would replace 4000-6000 L batch reactors.

Continuous Flow Barbier Reaction

Figure 2. Continuous Barbier Laboratory Setup

For 100 years, Grignard reactions have been one of the most powerful and effi cient organic chemistry methodologies for C-C bond formation. However, Grignard reactions are also among the most challenging reactions from both operational and potential safety issues due to initiation diffi culties and runaway potential. A close variation to the Grignard reaction is the Barbier reaction wherein the Grignard reagent is prepared in the presence of an electrophile resulting in the immediate consumption of the Grignard. A Barbier reaction using a CSTR was developed for a key pharmaceutical intermediate in production of edivoxetine·HCl (Scheme 4) [9]. In the fl ow setup (Figure 2), solid magnesium is sequestered in the fi rst tank where the Grignard initiation event takes place. CSTR 2 was used as an aging tank and CSTR 3 was the quench tank. CSTRs were used for Grignard reaction rather than a PFDR because of the solid Mg reagent.

Scheme 4: Barbier Reaction to form Ketone 15

Continuous reaction improved process safety, product quality, and process greenness. The continuous reaction achieved >99% ee in situ versus 95% ee batch because of immediate conversion of unstable intermediate. Solvent volumes were reduced 30%. The safety hazards were reduced by decreasing the reactor size by 50X, which reduced chemical potential and also increased heat transfer surface area per unit volume by 4X. DIBAL-H initiating agent was reduced by more than 100X, and excess Mg that must be quenched at the end of reaction was almost eliminated. When run continuously, the commercial scale Grignard formation reactor was expected to be 50L, which replaces 4000-6000L batch reactor.

The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

Michael E. Kopach,*^a Dilwyn J. Roberts,^a Martin D. Johnson,^a Jennifer McClary Groh,^a Jonathan J. Adler,^b John P. Schafer,^b Michael E. Kobierski^a and William G. Trankle^a

*Corresponding authors

^aChemical Product Research and Development, Eli Lilly and Company, Indianapolis, USA
E-mail: kopach_michael@lilly.com

^bD&M Continuous Solutions, Indianapolis, USA

Green Chem., 2012,14, 1524-1536

DOI: 10.1039/C2GC35050E

http://pubs.rsc.org/en/Content/ArticleLanding/2012/GC/C2GC35050E#!divAbstract

Three vessel Grignard CSTR process train.

Grignard synthesis of compound 1.

Retrosynthesis of edivoxetine·HCl.

Flow diagram for the whole continuous process from amide 3 to product 1.

Continuous crystallization of compound 1.

Distillation and continuous crystallization of compound 1.

Entry, Rxn temp. (°C), Vol. ratio THF–toluene (%), Conversion (%), ee (%)

//////////The continuous flow, Barbier reaction, improved environmental alternative, Grignard reaction, FLOW SYNTHESIS

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Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

flow synthesis Comments Off

Aug 132016

Abstract Image

Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

Michael E. Kopach^*^†, Kevin P. Cole^†, Patrick M. Pollock^†, Martin D. Johnson^†, Timothy M. Braden^†, Luke P. Webster^†, Jennifer McClary Groh^†, Adam D. McFarland^†, John P. Schafer^‡, Jonathan J. Adler^‡, and Morgan Rosemeyer^‡

^† Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

^‡ D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00131, http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00131

*E-mail: kopach_michael@lilly.com.

//////////Flow Grignard, Lithiation, Screening Tools, Development, Continuous Processes, Benzyl Alcohol, Starting Material

Supporting Info

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Synthesis of a Precursor to Sacubitril Using Enabling Technologies

flow synthesis, SYNTHESIS Comments Off

Aug 112016

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Shing-Hing Lau^†, Samuel L. Bourne^†, Benjamin Martin^‡, Berthold Schenkel^‡, Gerhard Penn^‡, and Steven V. Ley^*^†

^† Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.

^‡ Novartis Pharma AG, Postfach, 4002 Basel, Switzerland

Org. Lett., 2015, 17 (21), pp 5436–5439

DOI: 10.1021/acs.orglett.5b02806, http://pubs.acs.org/doi/10.1021/acs.orglett.5b02806

*E-mail: svl1000@cam.ac.uk.

S.-H. Lau, S. L. Bourne, B. Martin, B. Schenkel, G. Penn, S. V. Ley, Org. Lett., 2015, 17 (21), pp 5436–5439

LCZ696 (sacubitril/valsartan) is a first-in-class combination of the angiotensin II receptor-blocker valsartan and the neprilysin inhibitor sacubitril. A recent head-to-head comparison of LCZ696 with enalapril in a double-blind trial was stopped early because the boundary for an overwhelming benefit with LCZ696 was crossed.As a result of this, LCZ696 was reviewed under the FDA’s priority review program and was granted approval on the July 7, 2015 to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA Class II–IV) and reduced ejection fraction.

LCZ696 is a complex aggregate comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively

(2R, 4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride 3

To a stirred solution of (2R, 4S)-5-(4-Biphenylyl)-2-methyl-4-(tert-butylsulfinylamino)valeric acid 14 (50.0 mg, 134 μmol) in absolute ethanol (0.4 mL) at 0 °C was added thionyl chloride (20 μL, 268 μmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed to yield 46.0 mg (99%) of titled compound 3 as a white solid.

1 H NMR (600 MHz, DMSO-d6) δ 8.17 (br. s, 3H), 7.66 (dd, J = 8.0, 7.4 Hz, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (2 H, t, J = 7.4 Hz, H15, 2H), 7.36 (1 H, d, J = 8.0 Hz, H15), 3.99 (q, J = 7.1 Hz, H18), 3.42 – 3.36 (m, H4, 1H), 3.04 (dd, J = 13.8, 5.5 Hz, 1H), 2.81 (dd, J = 13.8, 8.1 Hz, 1H), 2.77 – 2.70 (m, 1H), 1.86 (ddd, J = 14.3, 9.1, 5.0 Hz, 1H), 1.59 (ddd, J = 13.8, 8.1, 5.4 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 7.1 Hz, 3H).

13C NMR (151 MHz, CDCl3) δ 174.7, 139.7, 138.7, 135.5, 130.0, 129.0, 127.4, 126.8, 126.5, 60.1, 50.4, 38.1, 35.5, 35.0, 17.5, 13.9.

HRMS (ESI+ , m/z [M+H]+ ) Calcd for C20H26NO2 312.1964; found 312.1967;

HPLC. 97:3 d.r. (Daicel Chiralpak AD-H column; isocratic n-hexane/ethanol/methanol/trimethylamine 80/10/10/0.2; 40 o C; flow rate = 0.8 mL min-1 ; λ = 254 nm; run time = 23 mins; tR (2R, 4S) 97.07%; tR (2S,4R) 0.21%; tR (2S, 4S) 2.32%; tR (2R,4R) 0.40%)

13C NMR Ethyl (2R,4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoate hydrochloride 3

////////////Synthesis, Precursor, Sacubitril, Enabling Technologies, flow synthesis, valsartan, LCZ69

Supporting Info

Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

flow synthesis, SYNTHESIS Comments Off

Jul 152016

A method for synthesizing chiral lactams from chiral oxaziridines in continuous flow is described. The oxaziridines are readily available from cyclic ketones. Photolysis of the oxaziridines using the Booker-Milburn flow system provides conversion to the chiral lactams in good yield and short residence times. Application of this chemistry toward the synthesis of a chiral bicyclic lactam is described.

Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

John E. Cochran^* and Nathan Waal

Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00213

*E-mail: john_cochran@vrtx.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00213

John Cochran

Manager, Custom Synthesis Group at Vertex Pharmaceuticals

https://www.linkedin.com/in/john-cochran-00a86299

Experience

Research Fellow II (Manager, Custom Synthesis Group)

Vertex Pharmaceuticals

January 2000 – Present (16 years 7 months)Boston, MA

– Supervised 10 chemists (6 Ph.D., 2 M.S., 2 B.S)

– Synthesized starting materials, intermediates, and preclinical tox lots for medicinal chemistry on
multigram to kilogram scale.

– Synthesized standards for various assays

– Performed kilo-scale enzymatic reactions

– Used flow chemistry on kilo scale

– Worked with several outsourcing firms in Europe and Asia

– Designed and updated an internal group website used to communicate with stakeholders

– Experienced with DOE and reaction optimization

Medicinal Chemist

Vertex Pharmaceuticals

March 1996 – January 2000 (3 years 11 months)Cambridge, MA

– Supervised 4 chemists (2 M.S., 2 B.S.)

– Managed a lead generation team that synthesized hundreds of very potent and selective heterocyclic leads on several kinase programs including JNK3, GSK3, LCK, SYK, and JAK3.

– Chemistry Head of the p38 2nd-generation program.

– Designed and synthesized very potent and selective inhibitors of p38

– Designed synthetic routes for previously unknown substitution patterns on pyridine

– Made presentations to external collaborators on the program.

– Produced two clinical candidates that were substantially more potent and had much better physical
properties than the 1st-generation inhibitors.

– Filed several patents concerning the 1st-generation compounds and related scaffolds

Postdoctoral Research Associate

Emory University

January 1994 – February 1996 (2 years 2 months)Atlanta, GA

– Designed and researched a proposal to use Pummerer chemistry to synthesize furans and to apply
the methodology to lignin synthesis

– Authored and investigated a proposal to synthesize 2-aminofurans using Pummerer or diazo
chemistry and to use them to make highly substituted anilines, phenols, indoles, and the general
framework found in the Amaryllidaceae, Erythrina, Lycopodium, and Aspidospermina classes of
alkaloids.

– Designed the synthetic strategy for indole synthesis using a vinylogous Pummerer rearrangement.

– Authored and supervised the research on a proposal to use Pummerer chemistry to synthesize
aromatic glides that can be used to make complex polycyclic systems.

– Supervised two graduate students working on the 2-aminofuran project and one graduate student on the vinylogous Pummerer project.

Industrial Chemist

Tennessee Valley Authority

1982 – 1988 (6 years)Muscle Shoals, AL

– Synthesized potential urease inhibitors in gram to several hundred gram quantities using high
temperature and high pressure equipment

– Performed gas-phase reactions in fluidized bed reactors containing transition-metal catalysts to find
an efficient industrial process for making dicyandiamide

– Characterized compounds and analyzed their decomposition kinetics using 1H and 31P NMR, HPLC,
and GC.

– Authored and researched a proposal to modify urea crystal morphology in fluid fertilizers

– Developed software for receiving and analyzing data from various instrumentation.

Education

University of Wisconsin-Madison

Doctor of Philosophy (Ph.D.), Organic Chemistry

1988 – 1993

Synthesized heterocyclophanes and studied their binding interactions with small neutral molecules in nonaqueous media. Complexation studies were performed with 1H , 13C, variable temperature, and 2D NMR, UV spectroscopy, and X-ray diffraction.