- Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis
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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.
- ?asar, Zdenko,Cluzeau, Jér?me,Kova?evi?, Miroslav Planinc,Nettekoven, Ulrike
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- Three-Step Total Synthesis of Ramelteon via a Catellani Strategy
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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.
- Gao, Shijun,Qian, Guangyin,Tang, Hao,Yang, Zuo,Zhou, Qianghui
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p. 5762 - 5765
(2019/11/03)
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- A process for the preparation of key intermediate lei meiti amine, its preparation and use
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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.
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- Preparation method of high-purity ramelteon
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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.
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- A lightning-US for amine method for the preparation of (by machine translation)
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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.
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- A novel and practical synthesis of ramelteon
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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.
- Xiao, Sa,Chen, Chao,Li, Hongyan,Lin, Kuaile,Zhou, Weicheng
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p. 373 - 377
(2015/03/30)
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- Synthesis of the melatonin receptor agonist Ramelteon using a tandem C-H activation-alkylation/Heck reaction and subsequent asymmetric Michael addition
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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.
- Fu, Xiaodan,Guo, Xingqun,Li, Xingwei,He, Lidong,Yang, Yushe,Chen, Youxi
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p. 827 - 832
(2013/08/23)
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- Stereoselective synthesis of melatonin receptor agonist ramelteon via asymmetric michael addition
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Highly enantioselective asymmetric Michael addition was used to synthesize ramelteon and its analogue. The asymmetric strategy provides an efficient approach for the medicinal modification of ramelteon with high ee value.
- Zhang, Xuan,Yuan, Wei,Luo, Yu,Huang, Qing-Qing,Lu, Wei
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- A NOVEL PROCESS FOR SYNTHESIS OF RAMELTEON, AND KEY INTERMEDIATES FOR THE SYNTHESIS OF RAMELTEON
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The present invention relates to a novel process for synthesis of ramelteon, and key intermediates for the synthesis of ramelteon.
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- PROCESS FOR THE PREPARATION OF RAMELTEON
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The present invention relates to a process for the preparation of ramelteon using 2- [(8S)-1, 6,7, 8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethanamine of Formula I or a salt thereof as an intermediate.
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Page/Page column 12-13
(2011/04/14)
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- PROCESS FOR THE SYNTHESIS OF RAMELTEON AND ITS INTERMEDIATES
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The present invention provides processes and intermediates for the synthesis of ramelteon.
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Page/Page column 35
(2010/04/30)
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- PROCESS FOR PREPARATION OF (S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO[5,4-B]FURAN-8-YL)ETHYL] PROPIONAMIDE AND NOVEL INTERMEDIATES THEREOF
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Disclosed herein process for preparation of (S)-Ramelteon and intermediates thereof.
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Page/Page column 33
(2010/04/28)
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- PROCESS FOR THE PREPARATION OF RAMELTEON
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A process is described for the preparation on an industrial scale of N-[2-(8S)- 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl] propionamide, ramelteon, having the structure illustrated below: (I).
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Page/Page column 38
(2010/10/03)
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- PROCESS FOR THE PREPARATION OF RAMELTEON
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A process is described for the preparation on an industrial scale of N-[2-(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propionamide, ramelteon, having the structure illustrated below:
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Page/Page column 15-16
(2010/09/18)
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- SYNTHESIS OF (S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO-[5,4-B]FURAN-8-YL)ETHYL]PROPIONAMIDE
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The present invention relates in general to the field of organic chemistry and in particular to the preparation of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, i.e. ramelteon, and analogues thereof.
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Page/Page column 23-24
(2010/09/03)
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- PROCESS FOR THE PREPARATION OF RAMELTEON
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Disclosed herein is a process for resolving N-[2-(1, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)] ethylamine into its isomers using an optically active acid and a process for preparing ramelteon from the resolved isomer.
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Page/Page column 11
(2010/06/15)
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- PROCESS FOR PREPARING RAMELTEON.
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The invention relates to an improved process for preparing indane derivatives including, for example, ramelteon. The invention provides a process for preparing ramelteon from a compound of formula (II), wherein the process comprises successive reduction reactions and converting a compound of formula (IV) to ramelteon: The invention further relates to an improved process for converting a compound of formula (IV) to ramelteon.
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- Polymorphic forms of ramelteon and processes for preparation thereof
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An amorphous form of ramelteon is provided, as well as mixtures of amorphous and crystalline ramelteon. Also provided are methods of preparing amorphous ramelteon and mixtures of amorphous and crystalline ramelteon, pharmaceutical compositions comprising amorphous ramelteon and mixtures of amorphous and crystalline ramelteon, and methods of treatment of insomnia using the compositions of the invention.
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Page/Page column 8
(2009/05/29)
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- PROCESS FOR THE SYNTHESIS OF RAMELTEON AND ITS INTERMEDIATES
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A process for the preparation of ramelteon and intermediates useful in the process. The process suitable for industrial scale provides increased yield and/or greater purity with fewer process steps.
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Page/Page column 17
(2009/12/04)
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- Synthesis of melatonin receptor agonist Ramelteon via Rh-eatalyzed asymmetric hydrogenation of an allylamine
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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
- Yamashita, Masayuki,Yamano, Toru
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scheme or table
p. 100 - 101
(2009/12/03)
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- PROCESS OF MAKING RAMELTEON AND RELATED SUBSTANCES
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The present patent application provides a process for the preparation of compounds of the Formula (I) Wherein represents a single bond or a double bond. R represents ethyl, vinyl or ethynyl.
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- PROCESS FOR THE SYNTHESIS OF RAMELTEON AND ITS INTERMEDIATES
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The present invention provides processes and intermediates for the synthesis of ramelteon.
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- PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE AMINE DERIVATIVES
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An industrial process for production of high-purity optically active amine derivatives in high yield while inhibiting the formation of by-products, which comprises subjecting (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine to asymmetric reduction, catalytically reducing the obtained product at a reaction temperature of 40 to 100°C and a pH of 3 to 9, subjecting the obtained (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine to propionylation, and then crystallizing the reaction mixture.
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Page/Page column 16
(2008/06/13)
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- Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation
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Asymmetric synthesis of a novel non-benzodiazepine hypnotic drug Ramelteon (TAK-375) was accomplished via asymmetric hydrogenation. Development of the substrate design revealed that a novel class of substrate, allylic acylamine 4a, was hydrogenated with a Ru-BINAP catalyst in 95% ee and 98% yield. The effectiveness and robustness of the reaction were demonstrated on a 700-g scale.
- Yamano, Toru,Yamashita, Masayuki,Adachi, Mari,Tanaka, Mitsutaka,Matsumoto, Kiyoharu,Kawada, Mitsuru,Uchikawa, Osamu,Fukatsu, Kohji,Ohkawa, Shigenori
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p. 184 - 190
(2007/10/03)
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- Pharmaceutical preparation containing copolyvidone
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A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.
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- PHARMACEUTICAL PREPARATION CONTAINING COPOLYVIDONE
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A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.
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- Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists
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To develop a new therapeutic agent for sleep disorders, we synthesized a novel series of tricyclic indan derivatives and evaluated them for their binding affinity to melatonin receptors. In our previous paper, we proposed a conformation of the methoxy group favorable for the binding of the MT1 receptor. To fix the methoxy group in an active conformation, we decided to synthesize conformationally restricted tricyclic indan analogues with the oxygen atom in the 6-position incorporated into a furan, 1,3-dioxane, oxazole, pyran, morpholine, or 1,4-dioxane ring system. Among these compounds, indeno[5,4-b]furan analogues were found to be the most potent and selective MT1 receptor ligands and to have superior metabolic stability. The optimization of substituents led to (S)-(-)-22b, which showed very strong affinity for human MT1 (Ki = 0.014 nM), but no significant affinity for hamster MT3 (Ki = 2600 nM) or other neurotransmitter receptors. The pharmacological effects of (S)-(-)-22b were studied in experimental animals, and it was found that a dose of 0.1 mg/kg, po promoted a sleep in freely moving cats, as demonstrated by a decrease in wakefulness and increases in slow wave sleep and rapid eye movement sleep, which lasted for 6 h after administration. Melatonin (1 mg/kg, po) also had a sleep-promoting effect, though it lasted only 2 h. A new chiral method for the synthesis of (S)-(-)-22b starting from 60, which was prepared from 59 employing asymmetric hydrogenation with the (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-Ru complex, was developed. (S)-(-)-22b (TAK-375) is currently under clinical trial for the treatment of insomnia and circadian rhythm disorders.
- Uchikawa, Osamu,Fukatsu, Kohji,Tokunoh, Ryosuke,Kawada, Mitsuru,Matsumoto, Kiyoharu,Imai, Yumi,Hinuma, Shuji,Kato, Koki,Nishikawa, Hisao,Hirai, Keisuke,Miyamoto, Masaomi,Ohkawa, Shigenori
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p. 4222 - 4239
(2007/10/03)
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- Bicyclic compounds and pharmaceutical composition containing tricyclic compound for treating or preventing sleep disorders
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A compound having the following general fomula: wherein R1 is an optionally substituted hydrocarbon, amino or heterocyclic group; R2 is H or an optionally substituted hydrocarbon group; R3 is H or an optionally substituted hydrocarbon or heterocyclic group; X is CHR4, NR4, O or S in which R4 is H or an optionally substituted hydrocarbon group; R5 is H, a halogen atom, C1-6 alkyl group, a C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group or an amino group wherein the C1-6 alkyl group, the C1-6 alkoxy group and the amino group may be substituted by 1 to 5 substituents, Y is C or N; ring B is an optionally substituted benzene ring; m = 1 to 4 and n = 0 to 2; L represents a leaving group such as a halogen atom, an alkylsulfonyl group, an alkylsulfonlyoxy group and arylsulfonyloxy group; or a salt thereof.
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- Method for treating or preventing sleep disorders
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The present invention provides a pharmaceutical composition for treating or preventing sleep disorders which comprises (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam.
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- Tricyclic compounds, their production and use
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A compound of the formula: STR1 wherein R1 is an optionally substituted hydrocarbon, amino or heterocyclic group; R2 is H or an optionally substituted hydrocarbon group; R3 is H or an optionally substituted hydrocarbon or heterocyclic group; X is CHR4, NR4, O or S in which R4 is H or an optionally substituted hydrocarbon group; Y is C, CH or N; ring A is optionally substituted 5- to 7-membered ring; ring B is an optionally substituted benzene ring; and m is 1 to 4, or a salt thereof, a process for producing it, an intermediate for the production and a pharmaceutical composition comprising it are provided.
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