A Novel and Practical Synthesis of Ramelteon

New Drug Approvals

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


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

Publication Date (Web): January 15, 2015 (Letter)
DOI: 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 …


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.