A Novel and Practical Synthesis of Ramelteon

New Drug Approvals

Ramelteon.svgRAMELTEON
Abstract Image

An efficient and practical process for the synthesis of ramelteon 1, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one 2 and the subsequent hydrogenation which successfully implement four processes (debromination, dehydration, olefin reduction, and cyano reduction) into one step to produce the ethylamine compound 13where dibenzoyl-l-tartaric acid is selected both as an acid to form the salt in the end of hydrogenation and as the resolution agent. Then, target compound 1 is easily obtained from13 via propionylation. The overall yield in this novel and concise process is almost twice as much as those in the known routes, calculated on compound 2.

A Novel and Practical Synthesis of Ramelteon

State Key Lab…

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Two-Step Cyanomethylation Protocol: Convenient Access to Functionalized Aryl- and Heteroarylacetonitriles

Figure

Two-Step Cyanomethylation Protocol: Convenient Access to Functionalized Aryl- and Heteroarylacetonitriles

Publication Date (Web): January 15, 2015 (Letter)
DOI: 10.1021/ol503479g

http://pubs.acs.org/doi/abs/10.1021/ol503479g

 

A two-step protocol has been developed for the introduction of cyanomethylene groups to metalated aromatics through the intermediacy of substituted isoxazoles. A palladium-mediated cross-coupling reaction was used to introduce the isoxazole unit, followed by release of the cyanomethylene function under thermal or microwave-assisted conditions. The intermediate isoxazoles were shown to be amenable to further functionalization prior to deprotection of the sensitive cyanomethylene motif, allowing access to a wide range of aryl- and heteroaryl-substituted acetonitrile building blocks.

Eli Lilly has officially opened new research facilities at its R&D base in Erl Wood in Surrey.

Eli Lilly and Company has announced a five year research partnership with the University of Surrey to study health outcomes, focusing on the effects of …

surrey

Logistics of process R&D: transforming laboratory methods to manufacturing scale

New Drug Approvals

The manufacture of a | omeprazole (racemic product; top), and esomeprazole (the (S)-enantiomer; bottom), including b | a flow chart of the process for the …

Nature Reviews Drug Discovery2, 654-664(August 2003) | doi:10.1038/nrd1154

Logistics of process R&D: transforming laboratory methods to manufacturing scale

Hans-Jürgen Federsel

In the past, process R&D — which is responsible for producing candidate drugs in the required quantity and of the requisite quality — has had a low profile, and many people outside the field remain unaware of the challenges involved. However, in recent years, the increasing pressure to achieve shorter times to market, the demand for considerable quantities of candidate drugs early in development, and the higher structural complexity — and therefore greater cost — of the target compounds, have increased awareness of the importance of process R&D. Here, I discuss the role of…

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Structure property calculation in apps: MMDS

Cheminformatics 2.0

mmds_propcalcs00An important milestone in has been reached in the migration of complicated structure-based calculations to pure mobile. The latest version of MMDS (1.5.9) is now available on the AppStore, and allows visualisation of calculated properties for individual molecules, as well as calculating new columns for entire datasheets.

The previous post described how recent porting of core technology (e.g. substructure query fragment searching) to Objective-C and iOS has opened the door to a variety of calculation types, including atom type-based contribution methods, while the post before that described how the porting of modern fingerprint types has enabled Bayesian models to be used. These progressions are significant, because the previous method of choice for carrying out difficult (or resource intensive) calculations was to hand off the data to a webservice, and await a response. The two technical arguments in favour of taking this approach are slowly but surely eroding: as device…

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“Straightforward and Versatile Synthesis of Fullerooxazoles from C60 and Carboxamides through Radical Reactions under Mild Conditions”

“Straightforward and Versatile Synthesis of Fullerooxazoles from C60 and Carboxamides through Radical Reactions under Mild Conditions”
Youhei Takeda, Satoru Enokijima, Toshiki Nagamachi, Kazuhisa Nakayama, and Satoshi Minakata*
Asian J. Org. Chem. 2013, 2, 91–97. DOI: 10.1021/ajoc.201200114

* Highlighted in ChemistryViews as a “Noteworthy Paper”! see the detail
* Highlighted in “ワイリー・サイエンスカフェ”!link

* Selected as the “Cover Picture” of the issue (Jan 10, 2013)!
* Ranked as the most-accessed article for February, March, April and May 2013 in a row!see the detail

Abstract: A direct synthetic method for producing oxazoline-fused fullerenes, that is, fullerooxazoles, from [60] fullerene and readily available carboxamides by radical pathways has been developed. The method presented allows efficient access to a variety of fullerooxazoles with high functional compatibility under mild reaction conditions. Furthermore, systematic investigation of their properties, such as solubility, thermostability, and electrochemical behavior, was conducted.

“Oxidative Dimerization of (Hetero)aromatic Amines Utilizing t‐BuOI Leading to (Hetero)aromatic Azo Compounds: Scope and Mechanistic Studies”

“Oxidative Dimerization of (Hetero)aromatic Amines Utilizing t‐BuOI Leading to (Hetero)aromatic Azo Compounds: Scope and Mechanistic Studies”
Sota Okumura, Chun-Hsuan Lin, Youhei Takeda*, and Satoshi Minakata*
J. Org. Chem.. 2013, 78, 12090–12105. DOI: 10.1021/jo402120w

Abstract: A straightforward synthetic method of both symmetric and unsymmetric aromatic azo compounds through an efficient and cross-selective oxidative dimerization of aromatic amines using tert-butyl hypoiodite (t-BuOI) under metal-free and mild conditions has been developed. This method was also found applicable to the synthesis of heteroaromatic azo compounds. The spectroscopic study indicates the involvement of N,N-diiodoanilines in the oxidative reaction as the key intermediate.

Complexation of enalapril maleate with b-cyclodextrin: NMR spectroscopic study in solution

A detailed NMR (1H , COSY, ROESY) spectroscopic study of complexation of enalapril maleate with b-cyclodextrin was carried out. The 1H NMR spectrum of enalapril maleate confirmed the existence of cis-trans equilibrium in solution, possibly due to hindered rotation along the amide bond. The cis-trans ratio remained almost the same in the presence of b-cyclodextrin but in one case it was found significantly different which suggests a catalytic role of b-cyclodextrin in the isomerization. 1H NMR titration studies confirmed the formation of an enalapril-b-cyclodextrin inclusion complex as evidenced by chemical shift variations in the proton resonances of both the host and the guest. The stoichiometry of the complex was determined to be 2:1 (guest: host). The mode of penetration of the guest into the b-cyclodextrin cavity as well as the structure of the complex were established using ROESY spectroscopy.

Química Nova

Print version ISSN 0100-4042

Quím. Nova vol.29 no.4 São Paulo July/Aug. 2006

http://dx.doi.org/10.1590/S0100-40422006000400011

http://www.scielo.br/scielo.php?pid=S0100-40422006000400011&script=sci_arttext

Complexation of enalapril maleate with b-cyclodextrin: NMR spectroscopic study in solution

Syed Mashhood Ali*, I; Arti MaheshwariI; Fahmeena AsmatI; Mamoru KoketsuII

IDepartment of Chemistry, Aligarh Muslim University, Aligarh 202002 (UP), India
IIDivision of Instrumental Analysis, Life Science Research Center, Gifu University, Gifu, 501-1193, Japan

* e-mail: smashhoodali@yahoo.com

Enalapril maleate, which exists in two geometrical forms in solution, forms a 1: 2 host-guest inclusion complex with b-CD in the concentration range studied. The aromatic ring of one guest molecule enters the b-CD cavity from narrower rim side while 5-membered ring penetrates through wider rim side as evidenced by ROESY spectrum. The structure for the complex has been proposed.

Zinc-Catalyzed Reactions of Ethenetricarboxylates with 2-(Trimethylsilylethynyl)anilines Leading to Bridged Quinoline Derivatives

Zinc-Catalyzed Reactions of Ethenetricarboxylates with
2-(Trimethylsilylethynyl)anilines Leading to Bridged Quinoline Derivatives

Shoko Yamazaki, Satoshi Morikawa, Kazuya Miyazaki, Masachika Takebayashi
Yuko Yamamoto, Tsumoru Morimoto, Kiyomi Kakiuchi, Yuji Mikata
Org. Lett. 2009, 11,13, 2796-2799.

http://pubs.acs.org/doi/abs/10.1021/ol900960q

Highlighted in .
ChemInform 2009, 40(46)http://onlinelibrary.wiley.com/doi/10.1002/chin.200946157/abstract

Zinc Lewis acid-catalyzed cyclization of ethenetricarboxylate derivatives 1 with 2-ethynylanilines has been examined. Reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate1b with 2-(trimethylsilylethynyl)aniline substrates in the presence of Zn(OTf)2 gave bridged quinoline derivatives in 43−85% yield. The reaction of 1b with 2′-aminoacetophenone also gave the bridged quinoline derivative in 41% yield. Thermal reaction of bridged quinolines (180−190 °C) afforded indole derivatives in moderate to good yields.

Michael J. McGlinchey

Photo

Michael J. McGlincheyBSc (1965), PhD (1968). Manchester, UK
Professor of Chemistry (Emeritus)
Fellow of the Chemical Institute of Canada (1985)
Alcan Award of the Canadian Society for Chemistry (2000)
 
 
 

The 600 MHz 1H-1H COSY spectrum of 23 showing four individual colour-coded spin systems.

Symmetry 06 00622f11a 1024

9-(1-naphthyl)-10-phenylanthracene, 23,

ChemSpider 2D Image | 9-(1-Naphthyl)-10-phenylanthracene | C30H20

In ascending order, sections of the 125 MHz 13C NMR spectra of 9-(2-indenyl)triptycene, η6-Cr complex, 43, η5-Cr complex, 44, and the analogous η5-Mn and η5-Re complexes. Free rotation of the triptycene paddlewheel in the free ligand and the η6-Cr complex, 43, allows the ring junction carbons, labeled in green and blue, to maintain their three-fold symmetry. In the η5-Cr, η5-Mn and η5-Re complexes these resonances are split into distinctive 2:1 patterns in accord with their CS symmetry.

Indenyl- and alkene-rotations interconvert different pairs of alkene protons in 26.

Symmetry 20146(3), 622-654; doi:10.3390/sym6030622


michael.mcglinchey@ucd.ie
School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland


School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland; E-Mail: michael.mcglinchey@ucd.ie; Tel.: +353-1-716-2165; Fax: +353-1-716-1178
http://www.chemistry.mcmaster.ca/mcglinchey/index.htm
http://chemistry.ucd.ie/mcglinchey/
http://www.chemistry.mcmaster.ca/mcglinchey/index.htm

Photo

Michael J. McGlincheyBSc (1965), PhD (1968). Manchester, UK
Professor of Chemistry (Emeritus)
Fellow of the Chemical Institute of Canada (1985)
Alcan Award of the Canadian Society for Chemistry (2000)

Michael McGlinchey was born in 1944 in Manchester, UK, and graduated in 1965 from the University of Manchester, Institute of Science & Technology (UMIST) with a BSc (Hons) in Chemistry. He did his graduate work at UMIST with Eric Banks on fluorinated azides and alkyl-nitrenes. He received his PhD in 1968, then went to the University of Bristol (UK) as a Junior Fellow and began to learn organometallic chemistry in Gordon Stone‘s laboratory. In 1970, he moved to Pennsylvania State University as a Research Associate working with Phil Skell, the renowned carbene chemist and, in 1972, was appointed Assistant Professor at McMaster University. He is currently a Professor in the Department of Chemistry. He has served as Chair of the Department, and as Chair of the Inorganic Division of the Canadian Society for Chemistry.
Over the past two decades, he has held numerous invited or visiting professorships at the Universities of Geneva and Lausanne in Switzerland, atRennesParisVersailles and Toulouse in France, and at the University of Heilongjiang in the north-east of China. He also received an Honorary Professorship from Siping Normal University in Jilin Province, China.
He and his wife Barbara have been married since 1970 and have two sons, Andrew and Paul.

Effective September, 2002 Prof. McGlinchey moved to: Department of ChemistryUniversity College Dublin, Ireland
For contact information in Dublin, see http://chemistry.ucd.ie/mcglinchey/



Variable-temperature NMR spectroscopy is probably the most convenient and sensitive technique to monitor changes in molecular structure in solution. Rearrangements that are rapid on the NMR time-scale exhibit simplified spectra, whereby non-equivalent nuclear environments yield time-averaged resonances. At lower temperatures, when the rate of exchange is sufficiently reduced, these degeneracies are split and the underlying “static” molecular symmetry, as seen by X-ray crystallography, becomes apparent. Frequently, however, such rearrangement processes are hidden, even when they become slow on the NMR time-scale, because the molecular point group remains unchanged. Judicious symmetry breaking, such as by substitution of a molecular fragment by a similar, but not identical moiety, or by the incorporation of potentially diastereotopic (chemically non-equivalent) nuclei, allows the elucidation of the kinetics and energetics of such processes. Examples are chosen that include a wide range of rotations, migrations and other rearrangements in organic, inorganic and organometallic chemistry.


Multiple Cope rearrangements equilibrate all ten CH positions in bullvalene.

Interconversion of distal and proximal ethyls, combined with rapid tripodal rotation, generates effective C6v symmetry.

Interconversions of the eight different indenyl ring environments in the RRR, RRS, RSS and SSS isomers of tri(indenyl)methylsilane, 32. The configurational inversion of a single indenyl ring requires two [1,5]-suprafacial sigmatropic shifts.

Symmetry-breaking plays a crucial role in many aspects of nuclear magnetic resonance spectroscopy. For example, theoreticians calculating the simplest spin-spin coupling constant, 1JHH in dihydrogen, need an experimental measurement to validate their predictions [1]. Evidently, this is not obtainable from H2 itself since the two nuclei are equivalent and the observed gas phase spectrum is a singlet. However, isotopic substitution, as in HD, yields duplicate values of 1JHD as 43.3 Hz, not only from the 1:1:1 triplet in the proton spectrum, but also from the 1:1 doublet in the deuterium spectrum (the nuclear spin values, I, for 1H and 2D are ½ and 1, respectively). The unobservable 1JHH is now readily calculated since 1JHH/1JHD = γHD = 6.51, where γ is the magnetogyric ratio for the relevant nucleus; the experimental value for 1JHH is therefore 282 Hz.
Variable-temperature NMR spectroscopy is probably the most convenient and widely-used technique to study molecular rearrangement processes in solution. It frequently allows elucidation not only of the mechanism of rearrangement, but also the activation energies and entropies of the process or processes involved. It is commonly the case that molecular rearrangements occur very rapidly at room temperature, thus equilibrating nuclear environments that are in fact non-equivalent in the static system, as seen for example by X-ray crystallography. Lowering the temperature slows the exchange processes on the NMR time-scale, thus revealing the underlying “instantaneous” structure and breaking the time-averaged symmetry.
Typically, bullvalene, 1, a C10H10 isomer (see Scheme 1), exhibits a single resonance in both the 1H and 13C NMR regimes at room temperature, but at low temperatures each is split into a 3:3:3:1 peak ratio [2], in accord with the solid state structure revealed by X-ray crystallography [3]. In this case, a series of rapid Cope rearrangements—[3,3] sigmatropic shifts in Woodward-Hoffmann orbital symmetry terminology [4]—in which each carbon can occupy any position, become slow on the NMR time-scale and so reveal the underlying C3v molecular geometry. However, there is no need to introduce additional labels to break the three-fold symmetry since it is immediately exposed merely by lowering the temperature.

– See more at: http://www.mdpi.com/2073-8994/6/3/622/htm

Group photo (95975 bytes)
The photograph shows the group in May 2000 at a Chinese restaurant.
Standing: Mike McGlinchey, Nicole Deschamps, Andrea Szkurhan, John Kaldis, Hari Gupta.
Seated: Stacey Brydges, Pippa Lock, Nada Reginato, Laura Ennis.
Since the picture was taken, Frank Ogini has joined the group.

siping.jpg (48719 bytes)
Receiving an Honorary Professorship at Siping Normal University, PR China

University College Dublin, Ireland

    1. Map of university college dublin
  1. University College Dublin


University College Dublin campus double-decker bus

dublin ireland

 
 
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