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
• General Description: Ramelteon is a selective melatonin MT1/MT2 receptor agonist developed by Takeda Pharmaceuticals North America, primarily used to treat circadian rhythm sleep disorders and insomnia. It is known by various names, including TAK-375 and Rozerem. The drug's synthesis has been optimized through enantioselective methods, such as asymmetric Michael addition, achieving high yields and enantiomeric purity. Alternative synthetic routes have also been developed, improving efficiency by consolidating multiple steps and avoiding costly reagents, thereby enhancing overall yield and practicality for large-scale production. These advancements support its therapeutic application and potential derivative modifications.

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

Stereoselective synthesis of melatonin receptor agonist ramelteon via asymmetric michael addition

10.3987/COM-11-12366

The study presents a highly enantioselective asymmetric Michael addition approach for synthesizing ramelteon and its analogues. Ramelteon, developed by Takeda Pharmaceuticals North America, is a selective agonist for the melatonin MT1/MT2 receptors, used for treating circadian rhythm sleep disorders. The study aims to develop an efficient synthetic method with high enantiomeric excess (ee) value. Key chemicals involved include α,β-unsaturated aldehydes and malonates, which are used in the asymmetric Michael addition to form chiral carbon-carbon bonds. The researchers optimized reaction conditions, finding that dimethyl malonate with a molar ratio of 2:1 to the aldehyde, a reaction temperature of 0-5 oC, and a 20% catalyst concentration over 48 hours yielded the best results, achieving a 94% yield and 96% ee for the intermediate compound 12. This optimized method was then applied to synthesize ramelteon and its analogues, demonstrating high efficiency and enantioselectivity, with the final product ramelteon achieving an enantiomeric ratio of 92%. The study concludes that this new synthetic approach is valuable for future medicinal modifications of ramelteon derivatives.

A novel and practical synthesis of ramelteon

10.1021/op500386g

The study outlines an efficient and practical synthesis process for ramelteon, a sedative-hypnotic drug used for treating insomnia. The novel synthesis involves the use of acetonitrile as a nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4b]furan-8-one, followed by a catalytic hydrogenation step that合并了debromination, dehydration, olefin reduction, and cyano reduction into one operation, resulting in the ethylamine compound. The process utilizes dibenzoyl-L-tartaric acid for salt formation and as a resolution agent, leading to the target compound ramelteon with an overall yield nearly double that of existing methods. The study emphasizes the avoidance of the traditional Wittig-Horner reaction, simplifying the synthesis with cost-effective reagents and reduced reaction steps.