Ramelteon

Base Information

• Chemical Name: Ramelteon
• CAS No.: 196597-26-9
• Molecular Formula: C16H21NO2
• Molecular Weight: 259.348
• European Community (EC) Number: 688-929-3,690-982-2
• UNII: 901AS54I69
• DSSTox Substance ID: DTXSID6045951
• Nikkaji Number: J1.473.195D
• Wikipedia: Ramelteon
• Wikidata: Q417689
• NCI Thesaurus Code: C66504
• RXCUI: 596205
• Pharos Ligand ID: 2XZYQRFDPBB2
• Metabolomics Workbench ID: 43232
• ChEMBL ID: CHEMBL1218
• Mol file: 196597-26-9.mol

Synonyms:Propanamide, N-(2-((8S)-1,6,7,8-tetrahydro-2H-indeno(5,4-b)furan-8-yl)ethyl)-;TAK-375;Rozerem;(S)-N-(2-(1,6,7,8-tetrahydro-2H-indeno-(5,4)furan-8-yl)ethyl)propionamide;(S)-N-[2-(1,6,7,8-Tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide(196597-26-9);

Chemical Property of Ramelteon

Chemical Property:

• Appearance/Colour: crystalline solid
• Vapor Pressure: 1.77E-08mmHg at 25°C
• Melting Point: 113-115 °C
• Refractive Index: 1.555
• Boiling Point: 455.3 °C at 760 mmHg
• PKA: 16.37±0.46(Predicted)
• Flash Point: 229.2 °C
• PSA: 38.33000
• Density: 1.119 g/cm³
• LogP: 2.95850
• Storage Temp.: -20°C Freezer
• Solubility.: Dimethyl Sulfoxide, Ethanol, Methanol,
• XLogP3: 2.7
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 2
• Rotatable Bond Count: 4
• Exact Mass: 259.157228913
• Heavy Atom Count: 19
• Complexity: 331

Purity/Quality:

99% ^*data from raw suppliers

Ramelteon ^*data from reagent suppliers

Safty Information:

• Pictogram(s): F,Xn
• Hazard Codes: F,Xn
• Statements: 11-20/21/22-36
• Safety Statements: 16-36/37

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Sedatives and Hypnotics
• Canonical SMILES: CCC(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3
• Isomeric SMILES: CCC(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3
• Recent ClinicalTrials: Delirium Reduction With Ramelteon
• Recent EU Clinical Trials: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Once a Day, TAK-375 (Ramelteon) Tablet for Sublingual Administration (TAK-375SL Tablet) 0.1 mg and 0.4 mg as an Adjunctive Therapy in the Treatment of Acute Depressive Episodes Associated With Bipolar 1 Disorder in Adult Subjects
• Recent NIPH Clinical Trials: Dosing-time-dependent effects of ramelteon on delirium prevention: a randomized controlled trial
• Description: Unlike most treatments of insomnia that target the GABA (g-aminobutyric acid) receptor complex, ramelteon is an agonist of the melatonin receptor. In particular, it has high selectivity for the MT1 and MT2 subtypes, which have been implicated in the maintenance of circadian rhythms, over the MT3 receptor responsible for other melatonin functions. Its lack of affinity for not only the GABA receptor complex but also neurotransmitter, dopaminerigic, opiate, and benzodiazepine receptors suggests an improved safety profile devoid of the abuse potential of the hypnotic drugs that target these receptors. As such, ramelteon is not a scheduled drug. Primary metabolites include hydroxylation and oxidation to carbonyl species with secondary metabolites resulting from glucuronidation. Since CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon, it should not be taken in combination with strong CYP1A2 inhibitors, such as fluvoxamine. Co-administration with either ketoconazole (a CYP3A4 inhibitor) or fluconazole (a potent CYP2C9 inhibitor) resulted in significant increases in AUC and Cmax, but the extensive metabolism and highly variable plasma concentrations of ramelteon precluded the need for dose modification. The package insert, however, cautions patients about co-administration with potent CYP3A4 and CYP2C9 inhibitors. Based on the result of the clinical trials, the recommended dose of ramelteon is 8mg taken within 30 min of going to bed. In addition to the precaution of co-administration with CYP inhibitors, it should not be used in patients with severe hepatic impairment. The adverse events, observed in 5% of patients in clinical studies, were somnolence, dizziness, nausea, fatigue, headache, and insomnia.
• Uses: Melatonin MT1/MT2 receptor agonist. Sedative, hypnotic melatonin receptor agonist

Technology Process of Ramelteon

There total 80 articles about Ramelteon which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 97.4%

(S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethylamine hydrochloride + propionyl chloride (79-03-8) → ramelteon (196597-26-9,196597-27-0,196597-17-8)

Guidance literature:

With sodium hydroxide; In tetrahydrofuran; water; at 20 ℃; for 1h;

Reference yield: 90.0%

(S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethylamine (196597-81-6) + propionyl chloride (79-03-8) → ramelteon (196597-26-9,196597-27-0,196597-17-8)

Guidance literature:

With triethylamine; In dichloromethane; at 0 - 20 ℃;

Reference yield: 86.0%

methanesulfonyl chloride (124-63-0) + (S)-N-[2-(6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl)ethyl]propionamide (196597-88-3) → ramelteon (196597-26-9,196597-27-0,196597-17-8)

Guidance literature:

methanesulfonyl chloride; (S)-N-[2-(6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl)ethyl]propionamide; With pyridine; at -10 - -5 ℃; for 0.833333h;

With triethylamine; In ethyl acetate; Further stages.; Heating;

DOI:10.1021/jm0201159

upstream raw materials:

(E)-3-(2,3-dihydrobenzofuran-4-yl)acrylaldehyde

(S)-dimethyl 2-(1-(2,3-dihydrobenzofuran-4-yl)-3-oxopropyl)malonate

(S)-3-(2,3-dihydrobenzofuran-4-yl)-5-methoxy-4-(methoxycarbonyl)-5-oxopentanoic acid

(S)-dimethyl 2-(6-oxo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)malonate

Downstream raw materials:

(S)-N-(2-[4-bromo-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl)propionamide

Refernces

• 1、 Gao, Shijun,Qian, Guangyin,Tang, Hao,Yang, Zuo,Zhou, Qianghui. "Three-Step Total Synthesis of Ramelteon via a Catellani Strategy". . p. 5762 - 5765. Retrieved 2019/11/03.
• 2、 -. "Preparation method of high-purity ramelteon". . . Retrieved 2017/08/14.