196597-17-8Relevant articles and documents
Synthesis of melatonin receptor agonist Ramelteon via Rh-eatalyzed asymmetric hydrogenation of an allylamine
Yamashita, Masayuki,Yamano, Toru
, p. 100 - 101 (2009)
In the course of developing a practical synthetic method for the selective melatonin MT1 /MT2 receptor agonist Ramelteon, a rhodium Josiphos complex was found to be an excellent catalyst for asymmetric hydrogenation of the key precursor, allylamine 1. Copyright
Three-Step Total Synthesis of Ramelteon via a Catellani Strategy
Gao, Shijun,Qian, Guangyin,Tang, Hao,Yang, Zuo,Zhou, Qianghui
, p. 5762 - 5765 (2019)
Ramelteon is the first medicine in human history that treat insomnia as a melatonin receptor agonist. Herein, we report an efficient three-step synthetic route to access it from commercially available 2,3-dihydrobenzofuran-4-amine, which represents as the shortest racemic synthesis to date with a 26 % overall yield. Key to the success is the application of the intermolecular Catellani-type alkylation and intramolecular redox-relay Heck cyclization cascade for preparation of the key indane-containing aldehyde. The unique primary amide-involved reductive amination of aldehyde is another feature of this route. New process of ramelteon can be developed based on this chemistry.
Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis
?asar, Zdenko,Cluzeau, Jér?me,Kova?evi?, Miroslav Planinc,Nettekoven, Ulrike
, (2021/10/20)
A concise six-step asymmetric synthesis of nearly enantiomerically pure ramelteon was developed from a monocyclic precursor with a 17% overall yield and a 97% ee in the asymmetric step. The synthetically challenging tricyclic 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan core of ramelteon was assembled by using Ir-catalyzed O-vinylation and Rh-catalyzed vinyl ether annulation through directed C-H bond activation, while the chirality was introduced with enantioselective reduction of an α,β-unsaturated nitrile moiety under hydrosilylation conditions using a CuII/Walphos type catalyst. The presented methodology represents the shortest synthetic approach to ramelteon.
A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides
Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels
supporting information, p. 7114 - 7123 (2021/03/03)
A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that 13C-labeled NiII-acyl complexes, formed from a 13CO insertion step with NiII-alkyl intermediates, rapidly react in less than one minute with 2,2’-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of 13C-SilaCOgen or 13C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired 13C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII-acyl complexes and the disulfide providing a reactive NiIII-acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.
Synthetic method of ramelteon
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, (2019/12/02)
The invention discloses a synthesis method of ramelteon. The method comprises the following steps: based on commercially available compounds 4-amino-2,3-dihydrobenzofuran, under the reacting functionof sulfuric acid, sodium nitrite and potassium iodide, an aryl ammonia compound is converted into an aryl iodine compound; allowing the obtained aryl iodine compound to react with a bromo allyl alcohol compound under the action of a palladium catalyst, an inorganic base, a phosphine ligand, a norbornene derivative and an additive to obtain an aldehyde group-containing ramelteon intermediate; finally, the intermediate and propionamide are subjected to a reductive amination reaction under the action of trifluoroacetic acid and triethylsilane, a target compound ramelteon is obtained, the reactioncomprises three steps in total, and the total yield is 26%. Compared with the prior art, the synthesis method disclosed by the invention has the advantages that the target molecule ramelteon can be obtained from the commercially available compound 4-amino-2, 3-dihydrobenzofuran which is easy to prepare only by three steps, the synthesis steps are greatly shortened compared with other process routes, the steps are few, and the safety is high.
A process for the preparation of key intermediate lei meiti amine, its preparation and use
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Paragraph 0128-0131, (2020/02/07)
The invention discloses critical intermediates (with the structure formula (I) ) used for preparing ramelteon. In the formula (I), A is O or S; R is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, phenyl, benzyl or p-methoxybenzyl; and when chiral carbon exists, the chemical compounds in the formula (I) are racemate or optically active compounds. When the A in the formula (I) is O and the R in the formula (I) is ethyl, the chemical compound is the chemical compound shown as the structure formula (II). In addition, the invention further discloses a preparing method of the chemical compound shown as the formula (II) and applications of the formula (II) in preparation of the ramelteon used for treating insomnia.
Preparation method of high-purity ramelteon
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, (2017/08/14)
The invention discloses a preparation method of high-purity ramelteon. The preparation method comprises the following steps: taking 1,2,6,7-tetrahydro-8H-indene[5,4-b]furan-8-ketone as a starting material; carrying out reduction and amino protection through wittig-horner reaction; carrying out amino deprotection under an acidic condition; carrying out hydrogenation reaction; then carrying out chiral resolution and acrylation reaction, thus obtaining the ramelteon. The ramelteon obtained through the invention is high in product purity and higher in yield; and formation of impurities is inhibited.
A lightning-US for amine method for the preparation of (by machine translation)
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Paragraph 0020; 0044-0046; 0051, (2017/05/18)
The invention relates to a preparation method of Ramelteon. The method mainly comprises three reaction steps of hydrogenation, chiral resolution and acylation reaction. According to the synthesis of the Ramelteon, 2-(1,6,7,8-tetralin-2H-indeno[5,4-b]furan-8-subunit) ethylamine hydrochloride serves as a start raw material, Pd-C serves as a catalyst, and 2-(1,6,7,8-tetralin-2H-indeno[5,4-b]furan-8-base) ethylamine hydrochloride, namely an midbody-1, is acquired through catalytic hydrogenation; chiral resolution is conducted on the midbody-1 through dibenzoyl-L-tartrate, so that (S)-2-(1,6,7,8-tetralin-2H-indeno[5,4-b]furan-8-base) ethylamine dibenzoyl-L-tartrate, namely a midbody-2, is acquired; an acylation reaction is conducted on the midbody-2 and propionyl chloride, so that a crude product of the Ramelteon is acquired, and a finished product of the Ramelteon is acquired after the crude product is refined and qualified.
A novel and practical synthesis of ramelteon
Xiao, Sa,Chen, Chao,Li, Hongyan,Lin, Kuaile,Zhou, Weicheng
, p. 373 - 377 (2015/03/30)
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 13 where 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 from 13 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.
Synthesis of the melatonin receptor agonist Ramelteon using a tandem C-H activation-alkylation/Heck reaction and subsequent asymmetric Michael addition
Fu, Xiaodan,Guo, Xingqun,Li, Xingwei,He, Lidong,Yang, Yushe,Chen, Youxi
, p. 827 - 832 (2013/08/23)
An asymmetric synthesis of the melatonin receptor agonist Ramelteon 1 has been achieved, which involved a tandem C-H activation-alkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily converted into Ramelteon 1 in 19% overall yield in 15 linear steps.
