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

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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

Day 10 of the 2016 Doodle Fruit Games! Find out more at g.co/fruit

MICONAZOLE NITRATE , Миконазол , ミコナゾール硝酸塩

New Drug Approvals


Miconazole            C18H14Cl4N2O    416.13             [22916478]

Miconazole Nitrate            C18H14Cl4N2O.HNO3              479.14             [22832877]

ミコナゾール硝酸塩 JP16
Miconazole Nitrate

C18H14Cl4N2O▪HNO3 : 479.14
[22832-87-7]


click on above image for clear view











MORE GRAPHS

13C





1D 1H, n/a spectrum for Miconazole

2D [1H,1H]-TOCSY  BELOW

2D [1H,1H]-TOCSY, n/a spectrum for Miconazole

1D DEPT90

1D DEPT90, n/a spectrum for Miconazole

1D DEPT135

1D DEPT135, n/a spectrum for Miconazole

2D [1H,13C]-HSQC

2D [1H,13C]-HSQC, n/a spectrum for Miconazole

2D [1H,13C]-HMBC

2D [1H,13C]-HMBC, n/a spectrum for Miconazole

2D [1H,1H]-COSY

2D [1H,1H]-COSY, n/a spectrum for Miconazole

2D [1H,13C]-HMQC

2D [1H,13C]-HMQC, n/a spectrum for MiconazoleMiconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or tomucous membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. It can also be used against certain species of Leishmania protozoa which are a type of unicellular parasites that…

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Directed alkynylation of unactivated C(sp3)-H bonds with ethynylbenziodoxolones mediated by DTBP

Green Chemistry International


Directed alkynylation of unactivated C(sp3)-H bonds with ethynylbenziodoxolones mediated by DTBP

Green Chem., 2016, 18,4185-4188

DOI: 10.1039/C6GC01336H, Communication
Zhi-Fei Cheng, Yi-Si Feng, Chun Rong, Tao Xu, Peng-Fei Wang, Jun Xu, Jian-Jun Dai, Hua-Jian Xu
A general and efficient alkynylation of unactivated C(sp3)-H bonds under metal-free conditions was developed herein.

Directed alkynylation of unactivated C(sp3)–H bonds with ethynylbenziodoxolones mediated by DTBP

Zhi-Fei Cheng,a  Yi-Si Feng,*abc  Chun Rong,a  Tao Xu,a  Peng-Fei Wang,a  Jun Xu,a  Jian-Jun Daia and  Hua-Jian Xu*abc  
*Corresponding authors
aSchool of Chemistry and Chemical Engineering, School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, P. R. China
bAnhui Key Laboratory of Controllable Chemical Reaction and Material Chemical Engineering, Hefei 230009, P. R…

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Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC01600F, Paper
Li Chen, Jinmo Zhao, Sivaram Pradhan, Bruce E. Brinson, Gustavo E. Scuseria, Z. Conrad Zhang, Michael S. Wong
The nonselective nature of glucose pyrolysis chemistry can be controlled by preventing the sugar ring from opening and fragmenting.

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

*Corresponding authors
aDepartment of Chemical and Biomolecular Engineering, Rice University, Houston, USA
E-mail: mswong@rice.edu
bDepartment of Chemistry, Rice University, Houston, USA
cDalian National Laboratory of Clean Energy, Dalian Institute of Chemical Physics, Dalian, China
E-mail: zczhang@dicp.ac.cn
dDepartment of Civil and Environmental Engineering, Rice University, Houston, USA
eDepartment of Materials Science and NanoEngineering, Rice University, Houston, USA
Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC01600F

The selective production of platform chemicals from thermal conversion of biomass-derived carbohydrates is challenging. As precursors to natural products and drug molecules, anhydrosugars are difficult to synthesize from simple carbohydrates in large quantities without side products, due to various competing pathways during pyrolysis. Here we demonstrate that the nonselective chemistry of carbohydrate pyrolysis is substantially improved by alkoxy or phenoxy substitution at the anomeric carbon of glucose prior to thermal treatment. Through this ring-locking step, we found that the selectivity to 1,6-anhydro-β-D-glucopyranose (levoglucosan, LGA) increased from 2% to greater than 90% after fast pyrolysis of the resulting sugar at 600 °C. DFT analysis indicated that LGA formation becomes the dominant reaction pathway when the substituent group inhibits the pyranose ring from opening and fragmenting into non-anhydrosugar products. LGA forms selectively when the activation barrier for ring-opening is significantly increased over that for 1,6-elimination, with both barriers affected by the substituent type and anomeric position. These findings introduce the ring-locking concept to sugar pyrolysis chemistry and suggest a chemical-thermal treatment approach for upgrading simple and complex carbohydrates.

////////Ring-locking ,  selective anhydrosugar, carbohydrate pyrolysis, synthesis

N-Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

N-Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

Green Chem., 2016, 18,3990-3996
DOI: 10.1039/C6GC00932H, Paper
James Sherwood, Helen L. Parker, Kristof Moonen, Thomas J. Farmer, Andrew J. Hunt
N-Butylpyrrolidinone (NBP) has been demonstrated as a suitable safer replacement solvent for N-Methylpyrrolidinone (NMP) in selected organic syntheses.

N-Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

*Corresponding authors
aGreen Chemistry Centre of Excellence, Department of Chemistry, University of York, UK
E-mail: andrew.hunt@york.ac.uk
bEastman Chemical Company, Pantserschipstraat 207 – B-9000, Gent, Belgium
Green Chem., 2016,18, 3990-3996

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00932H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract
DOI: 10.1039/C6GC00932H

Dipolar aprotic solvents such as N-methylpyrrolidinone (or 1-methyl-2-pyrrolidone (NMP)) are under increasing pressure from environmental regulation. NMP is a known reproductive toxin and has been placed on the EU “Substances of Very High Concern” list. Accordingly there is an urgent need for non-toxic alternatives to the dipolar aprotic solvents. N-Butylpyrrolidinone, although structurally similar to NMP, is not mutagenic or reprotoxic, yet retains many of the characteristics of a dipolar aprotic solvent. This work introduces N-butylpyrrolidinone as a new solvent for cross-coupling reactions and other syntheses typically requiring a conventional dipolar aprotic solvent.
STR1

//////////////N-Butylpyrrolidinone, dipolar aprotic solvent, organic synthesis

2-Bromo-1,4-benzenedimethanol

(2-bromo-4-hydroxymethylphenyl)methanol.png

(2-bromo-4-hydroxymethylphenyl)methanol;

 CAS 89980-92-7; 

2-Bromo-1,4-benzenedimethanol;

Molecular Formula: C8H9BrO2
Molecular Weight: 217.05986 g/mol

(2-Bromo-4-hydroxymethylphenyl)methanol (3).

To a solution of commercially available 2-bromoterephthalic acid (2) (575 g, 2.34 mol) in THF (5.75 L), a THF solution of BH3 (1.0 M, 5.86 L) was added at 0 °C dropwise for 2.5 h, and the mixture was stirred for 1 h at 0 °C. The mixture was gradually warmed up to 35 °C over 3.5 h. The reaction mixture was cooled to 0 °C and quenched by dropwise addition of MeOH (1.15 L) over 30 min. Then, the mixture was concentrated in vacuo. The residue was dissolved in MeOH (1.72 L), and then water (10.3 L) was added; the mixture was then stirred at 0 °C for 30 min. The off-white solid was filtered and washed with water (1.15 L × 3) and heptanes (2.30 L) to obtain 3 (426 g, 84%) as a white crystal;

mp 108–109 °C;

1H NMR (400 MHz, DMSO-d6) δ: 4.47 (2H, d, J = 5.6 Hz), 4.49 (2H, d, J = 5.4 Hz), 5.29 (1H, t, J = 5.6 Hz), 5.39 (1H, t, J = 5.4 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.48–7.49 (1H, m);

13C NMR (100 MHz, DMSO-d6) δ: 61.9, 62.5, 120.8, 125.5, 127.9, 129.7, 139.1, 143.4;

HRMS (EI) calcd for C8H9BrO2 [M]+ 215.9786, found 215.9787.

1H NMR

1H NMR (400 MHz, DMSO-d6) δ: 4.47 (2H, d, J = 5.6 Hz), 4.49 (2H, d, J = 5.4 Hz), 5.29 (1H, t, J = 5.6 Hz), 5.39 (1H, t, J = 5.4 Hz), 7.31 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.48–7.49 (1H, m); 

13C NMR

13C NMR (100 MHz, DMSO-d6) δ: 61.9, 62.5, 120.8, 125.5, 127.9, 129.7, 139.1, 143.4;

MASS PREDICT

1H/13C PREDICT

J. Org. Chem.201681 (5), pp 2148–2153

DOI: 10.1021/acs.joc.5b02734

///////////c1(cc(c(cc1)CO)Br)CO

An efficient Passerini tetrazole reaction (PT-3CR)

Green Chemistry International

Graphical abstract: An efficient Passerini tetrazole reaction (PT-3CR)

An efficient Passerini tetrazole reaction (PT-3CR)

Green Chem., 2016, 18,3718-3721

DOI: 10.1039/C6GC00910G, Communication

Ajay L. Chandgude, Alexander Domling

A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-type three-component reaction (PT-3CR) has been developed.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00910G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-type three-component reaction (PT-3CR) has been developed. It comprises the reaction of an aldehyde/ketone, an isocyanide and a TMS-azide in methanol : water (1 : 1) as the solvent system. The use of sonication not only accelerated the rate of the reaction but also provided good to excellent quantitative yields. This reaction is applicable to a broad scope of aldehydes/ketones and isocyanides.

An efficient Passerini tetrazole reaction (PT-3CR)

*
Corresponding authors
a
Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV…

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