AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Jun 052017
 

 

 

Abstract Image

The first continuous flow synthesis of C8–C16 alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting the molar ratio of substrates. By means of flow technique, a shorter reaction time, satisfactory output, and continuous preparation are achieved under the present procedure, representing a significant advance over the corresponding batch reaction conditions.

Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

Tao Shen, Jingjing Tang, Chenglun Tang, Jinglan Wu, Linfeng Wang, Chenjie Zhu*§ , and Hanjie Ying§
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
National Engineering Technique Research Center for Biotechnology, Nanjing 211816, China
§Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing 211816, China
State Key Laboratory of Motor Vehicle Biofuel Technology, Nanyang 473000, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00141

 

*E-mail: zhucj@njtech.edu.cn. Phone/Fax: +86 25 58139389.
1-(furan-2-yl)-2-methylpent-1-en-3-one
1a
3-pentanone (100 mmol, 8.6 g) and furfural (100 mmol, 9.6 g) were diluted with MeOH-H2O to 40 mL in stream 1, catalyst TBD (10 mmol, 1.39 g) were diluted with MeOH-H2O (v/v = 1/1) to 40 mL in stream 2, the two streams was purged in a 0.2 mL/min speed into slit plate mixer and at the 353 K passed tubing reactor. Finally, the product was extracted with EtOAc and water, the obtained organic layer was evaporated and purified by silica gel flash chromatography (25:1 hexane-EtOAc) to provide the analytically pure product for further characterization, the aqueous phase was collected and reused.According to the general procedure afforded 14.92 g (91%) of product 1a, isolated as pale yellow oil;
1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 1.4 Hz, 1H), 7.29 (s, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 2.71 (q, J = 7.3 Hz, 2H), 2.05 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CD3OD) δ 203.5, 153.0, 145.8, 133.8, 126.8, 116.6, 113.3, 31.1, 13.2, 9.2.
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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

 FLOW CHEMISTRY, flow synthesis, phase 1  Comments Off on Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement
Jan 212017
 

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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03123D, Paper
Maurice A. Marsini, Frederic G. Buono, Jon C. Lorenz, Bing-Shiou Yang, Jonathan T. Reeves, Kanwar Sidhu, Max Sarvestani, Zhulin Tan, Yongda Zhang, Ning Li, Heewon Lee, Jason Brazzillo, Laurence J. Nummy, J. C. Chung, Irungu K. Luvaga, Bikshandarkoil A. Narayanan, Xudong Wei, Jinhua J. Song, Frank Roschangar, Nathan K. Yee, Chris H. Senanayake
A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03123D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

*Corresponding authors
aDepartment of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, USA
E-mail: maurice.marsini@boehringer-ingelheim.com
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03123D

 

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1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

m.p. = 140-144 °C;

1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.93 (s, J1 = 8.8 Hz, J2 = 4.7 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J = 4.1 Hz, 1H), 7.49 (t, J = 8.7 Hz, 1H), 3.29 (s, 3H), 1.61 (bs, 4H);

13C NMR (100 MHz, CDCl3) δ 166.1, 162.7, 160.3, 158.4, 156.9, 150.6, 139.2, 138.2, 135.8, 135.6, 125.4 (d, JC-F = 8.8 Hz), 123.3, 121.9, 117.2 (d, JC-F = 23.1 Hz), 116.4, 40.2, 34.9, 20.9;

HRMS: calcd for C22H19FN5O3S [M + H+ ]: 452.1187. Found: 452.1189.

 

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//////////BI-638683, BI 638683, CCR1 antagonist, 295298-26-8, US2012270870, Boehringer Ingelheim Pharmaceuticals, phase 1

CS(=O)(=O)c1nccc(c1)C2(CC2)NC(=O)c5cncc3c5cnn3c4ccc(F)cc4

SCHEMBL1670702.png

Molecular Formula: C22H18FN5O3S
Molecular Weight: 451.476 g/mol

CCR1 antagonist

cas 295298-26-8

US2012270870

maybe BI-638683, not sure

In September 2010, a randomized, double-blind, placebo-controlled, phase I study (NCT01195688; 1279.1; 2010-021187-15) was initiated in healthy male volunteers (expected n = 64) in Germany, to assess the safety, pharmacokinetics and pharmacodynamics of BI-638683. The study was completed in December 2010 . In June 2014, data were presented at the EULAR 2014 Annual Meeting in Paris, France. A dose of 75-mg showed maximal inhibition of mRNA expression of the four-CC chemokine receptor type-I dependent marker genes. chemokine ligand -2  and Peroxisome proliferator-activated receptor gamma-mRNAs by doses of 300 mg and higher, and for Ras-related protein rab-7b mRNA by doses of 500 mg and higher

Boehringer Ingelheim was developing BI-638683, a CCR1 antagonist, for the potential oral treatment of rheumatoid arthritis. A phase I trial was completed in December 2010 . Phase I data was presented in June 2014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011049917&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Inventors Brian Nicholas Cook, Daniel Kuzmich, Can Mao, Hossein Razavi
Applicant Boehringer Ingelheim International Gmbh

Chemotactic Cytokine Receptor 1 (CCRl) belongs to a large family (>20) of chemotactic cytokine (chemokine) receptors that interact with specific chemokines (>50) to mediate leukocyte trafficking, granule exocytosis, gene transcription, mitogenic effects and apoptosis. Chemokines are best known for their ability to mediate basal and inflammatory leukocyte trafficking. The binding of at least three chemokines (MIP-1 alpha/CCL3, MCP3/CCL7 and RANTES/CCL5) to CCRl is responsible for the trafficking of monocytes, macrophages and THl cells to inflamed tissues of rheumatoid arthritis (RA) and multiple sclerosis (MS) patients (Trebst et al. (2001) American J of Pathology 159 p. 1701). Macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage chemoattractant protein 3 (MCP-3) and regulated on activation, normal T-cell expressed and secreted (RANTES) are all found in the CNS of MS patients, while MIP-1 alpha and RANTES are found in the CNS in the experimental autoimmune encephalomyelitis (EAE) model of MS (Review: Gerard

and Rollins (2001) Nature Immunology). Macrophages and Thl cells in the inflamed synovia of RA patients are major producers of MIP-1 alpha and RANTES, which continuously recruit leukocytes to the synovial tissues of RA patients to propagate chronic inflammation (Volin et al. (1998) Clin. Immunol. Immunopathology; Koch et al. (1994) J. Clin. Investigation; Conlon et al. (1995) Eur. J. Immunology). Antagonizing the interactions between CCR1 and its chemokine ligands is hypothesized to block chemotaxis of monocytes, macrophages and Thl cells to inflamed tissues and thereby ameliorate the chronic inflammation associated with autoimmune diseases such as RA and MS.

Evidence for the role of CCR1 in the development and progression of chronic inflammation associated with experimental autoimmune encephalitis (EAE), a model of multiple sclerosis, is based on both genetic deletion and small molecule antagonists of CCR1. CCR1 deficient mice were shown to exhibit reduced susceptibility (55% vs. 100%) and reduced severity (1.2 vs. 2.5) of active EAE (Rottman et al. (2000) Eur. J. Immunology). Furthermore, administration of small molecule antagonist of CCR1, with moderate affinity (K; = 120 nM) for rat CCR1, was shown to delay the onset and reduce the severity of EAE when administered intravenously (Liang et al. (2000) /. Biol. Chemistry). Treatment of mice with antibodies specific for the CCR1 ligand MIP- 1 alpha have also been shown to be effective in preventing development of acute and relapsing EAE by reducing the numbers of T cells and macrophages recruited to the CNS (Karpus et al. (1995) /. Immunology; Karpus and Kennedy (1997) /. Leukocyte Biology). Thus, at least one CCR1 ligand has been demonstrated to recruit leukocytes to the CNS and propagate chronic inflammation in EAE, providing further in vivo validation for the role of CCR1 in EAE and MS.

In vivo validation of CCR1 in the development and propagation of chronic inflammation associated with RA is also significant. For example, administration of a CCR1 antagonist in the collagen induced arthritis model (CIA) in DBA/1 mice has been shown to be effective in reducing synovial inflammation and joint destruction (Plater-Zyberk et al. (1997) Immunology Letters). Another publication described potent antagonists of murine CCR1 that reduced severity (58%) in LPS-accelerated collagen-induced arthritis (CIA), when administered orally {Biorganic and Medicinal Chemistry Letters 15, 2005, 5160-5164). Published results from a Phase lb clinical trial with an oral CCRl antagonist demonstrated a trend toward clinical improvement in the absence of adverse side effects (Haringman et al. (2003) Ann. Rheum. Dis.). One third of the patients achieved a 20% improvement in rheumatoid arthritis signs and symptoms (ACR20) on day 18 and CCRl positive cells were reduced by 70% in the synovia of the treated patients, with significant reduction in specific cell types including 50% reduction in CD4+ T cells, 50% reduction in CD8+ T cells and 34% reduction in macrophages.

Studies such as those cited above support a role for CCRl in MS and RA and provide a therapeutic rationale for the development of CCRl antagonists.

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

 FLOW CHEMISTRY, flow synthesis  Comments Off on Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions
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.

Figure

Figure

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

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

PIETRO TUNDO

logo unive

Tundo300X292

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).

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 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

////////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

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Continuous-Flow Diazotization

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous-Flow Diazotization
Nov 242016
 

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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.

 

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

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
Copyright © 2016 American Chemical Society
*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

Abstract

Abstract Image

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.

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

 flow synthesis  Comments Off on The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?
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?

*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 on Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material
Aug 132016
 

str1

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

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

 

 

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

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Synthesis of a Precursor to Sacubitril Using Enabling Technologies

 flow synthesis, SYNTHESIS  Comments Off on Synthesis of a Precursor to Sacubitril Using Enabling Technologies
Aug 112016
 

 

Abstract Image

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

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
Figure

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

Figure

(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

str1

str2 str1

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

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Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor

 flow synthesis, SYNTHESIS  Comments Off on Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor
Jun 242016
 
Abstract Image

The synthesis of hydroperoxymethyl oxazoles by oxidation of alkylideneoxazoles with molecular oxygen was implemented in a microstructured reactor for increased safety and larger-scale applications. Elaborate studies on the influence of pressure and temperature were performed, and the apparent activation energy for the oxidation reaction was determined. Elevated temperatures up to 100 °C and pressures up to 18 bar(a) led to a conversion rate of approximately 90% within 4 h of the reaction time, thus displaying the high potential and beneficial effect of using a microreactor setup with liquid recycle loop for this oxidation. The in situ reduction of the generated hydroperoxide functionality shows the capability of this setup for follow-up transformations.

Oxazole–hydroperoxide 3as a colorless solid. Rf (PE/EA 3:1 = 0.31).

1H NMR (30 MHz, CDCl3) δ = 4.98 (s, 2H), 7.12 (s, 1H), 7.49–7.29 (m, 3H), 7.88–7.75 (m, 2H), 10.16 (s, 1H). GC-MS (EI) m/z = 173.1 (M – OH), 144.1 (M – CH2OOH), 116.1 (M – C6H5 + 2H), 89.1.

 

STR1

Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor

Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,Germany
Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany
§ Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00118
*E-mail: t.roeder@hs-mannheim.de. Telephone: +49 621 292 6800.
Siegel
Organisch-Chemisches Institut                                    
Im Neuenheimer Feld 270
69120 Heidelberg
Germany
Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany

Panorama picture of the Campus in July 2006

 

Thorsten Röder

Prof. Dr.
Professor (Full)

Research experience

  • Sep 2009–present
    Professor (Full)
    Hochschule Mannheim · Institute of Chemical Process Engineering
    Germany · Mannheim
  • Sep 2005–Aug 2009
    Laboratory Head
    Novartis · Chemical and Analytical Process Development
    Switzerland · Basel
  • Sep 1999–Aug 2004
    PhD Student
    Universität Paderborn · Department of Chemistry · Physical Chemistry Prof. Kitzerow
    Germany · Paderborn
 Teaching experience
  • Sep 2009–present
    Professor (Full)
    Hochschule Mannheim · Institute of Chemical Process Engineering
    Germany
    Lectures in: Chemical Reaction Engineering Thermodynamic Microreactors & Nanotechnology CFD Practical Course: Chemical Reaction Engineering

Education

  • Oct 1999–Oct 2004
    Universität Paderborn
    Physical Chemistry · Dr. rer. nat.
    Germany · Paderborn
  • Sep 1994–Sep 1999
    Universität Paderborn
    Chemistry · Diplom Chemiker
    Germany
Hashmi Stephen 160x200

Prof. Dr. A. Stephen K. Hashmi

E-Mail hashmi@hashmi.de

/////////Safe and Fast,  Flow Synthesis, Functionalized Oxazoles, Molecular Oxygen, Microstructured Reactor

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Flow approach towards AZD 6906

 flow synthesis, PROCESS  Comments Off on Flow approach towards AZD 6906
May 272016
 
[1860-5397-11-134-i11]
Scheme 1: Flow approach towards AZD6906 (65).

PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry,  Marcus Baumann and Ian R. Baxendale, Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134

In 2012 researchers from AstraZeneca (Sweden) reported upon a scale-up campaign for their gastroesophageal reflux inhibitor programme. Specifically, flow chemical synthesis was used to efficiently and reliably provide sufficient quantities of the target compound AZD6906 (65), which had been prepared previously in batch. From these earlier batch studies concerns had been raised regarding exothermic reaction profiles as well as product instability which needed to be addressed when moving to larger scale synthesis. Flow was identified as a potential way of circumventing these specific problems and so was extensively investigated. The developed flow route [1 ] started with the reaction of methyl dichlorophosphine (66) and triethyl orthoacetate (67), which in batch could only be performed under careful addition of the reagent and external cooling using dry ice/acetone. Pleasingly, a simple flow setup in which the two streams of neat reagents were mixed in a PTFE T-piece maintained at 25 °C was found effective in order to prepare the desired adduct 68 in high yield and quality showcasing the benefits of superior heat dissipation whilst also safely handling the toxic and pyrophoric methyl dichlorophosphine reagent (Scheme 1).

As the subsequent Claisen condensation step was also known to generate a considerable exotherm, a similar flow setup was used in order to allow the reaction heat to dissipate. The superiority of the heat transfer process even allowed this step to be performed on kilogram quantities of both starting materials (68, 69) at a reactor temperature of 35 °C giving the desired product 72 within a residence time of only 90 seconds. Vital to the successful outcome was the efficient in situ generation of LDA from n-BuLi and diisopropylamine as well as the rapid quenching of the reaction mixture prior to collection of the crude product. Furthermore, flow processing allowed for the reaction of both substrates in a 1:1 ratio (rather than 2:1 as was required in batch) as the immediate quenching step prevented side reactions taking place under the strongly basic conditions. Having succeeded in safely preparing compound 72 on kilogram scale, the target compound 65 was then generated by global deprotection and subsequent recrystallisation where batch was reverted to as the conditions had been previously devised and worked well.

Marcus

Dr Marcus Baumann
Postdoc

Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.

Prof. Ian R. Baxendale

Personal web page

Professor in the Department of Chemistry
Telephone: +44 (0) 191 33 42185

(email at i.r.baxendale@durham.ac.uk)

Research Interests

My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.

My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.

For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/

Abstract Image

Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and starting materials could be handled in a flow regime, thereby allowing safer and more convenient reaction optimization and production.

Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Process Res. Dev. 2012, 16, 925–929. doi:10.1021/op200340c

Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906

Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
Org. Process Res. Dev., 2012, 16 (5), pp 925–929
DOI: 10.1021/op200340c
Publication Date (Web): February 21, 2012
Copyright © 2012 American Chemical Society
*Telephone: +46 31 776 16 65. Email: fritiof.ponten@astrazeneca.com.
This article is part of the Continuous Processes 2012 special issue.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture.  This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale.  One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative.  The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

 

////Flow synthesis,  AZD 6906

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