609799-22-6

Basic information

• Product Name: Tasimelteon
• Synonyms: tasimelteon;(1R-trans)-N-[[2-(2,3-Dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide;BMS 214778;MA 1;VEC 162;TasiMelteon/BMS214778;Tasimelteon (1R-trans)-N-[[2-(2,3-Dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide;tasimelteon impurity A
• CAS NO: 609799-22-6
• Molecular Formula: C₁₅H₁₉NO₂
• Molecular Weight: 245.32
• Product Categories: Pharmaceuticals
• Mol File: 609799-22-6.mol

Chemical Properties

• Melting Point: 78 °C
• Boiling Point: 442.553 ºC at 760 mmHg
• Flash Point: 221.448 ºC
• Appearance: /
• Density: 1.145
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.564
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 16.43±0.46(Predicted)
• CAS DataBase Reference: Tasimelteon(CAS DataBase Reference)
• NIST Chemistry Reference: Tasimelteon(609799-22-6)
• EPA Substance Registry System: Tasimelteon(609799-22-6)

Safety Data

• Hazardous Substances Data: 609799-22-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Tasimelteon is used as a therapeutic agent for the treatment of non-24-hour sleep-wake disorder, a circadian rhythm sleep disorder often seen in visually impaired patients. It helps correct the circadian rhythm disorder by targeting melatonin MT1 and MT2 receptors, with a greater affinity to the MT2 receptor.
Used in Clinical Trials:
Tasimelteon has been tested in two randomized controlled trials (phases II and III), which demonstrated its effectiveness in improving sleep latency and maintenance of sleep, as well as shifting circadian rhythms. This makes it a potential treatment for patients with transient insomnia associated with circadian rhythm sleep disorders.
Used in Preclinical Studies:
In preclinical studies, tasimelteon has shown similar phase-shifting properties to melatonin, but with less vasoconstrictive effects, making it a promising candidate for further research and development in the treatment of sleep disorders.

Synthesis

Activation of commercial bis-ethanol 250 with 2.5 equivalents of the Vilsmeier salt 251 followed by treatment with base resulted an intramolecular cyclization reaction with the proximal phenol and concomitant elimination of the remaining imidate to deliver the vinylated dihydrobenzofuran 252 in 76% yield. Interestingly, this reaction could be performed on multi-kilogram scale, required no chromatographic purification, and generated environmentallyfriendly DMF and HCl as byproducts. Sharpless asymmetric dihydroxylation of olefin 252 delivered diol 253 in 86% yield and impressive enantioselectivity (>99% ee). This diol was then activated with trimethylsilyl chloride and then treated with base to generate epoxide 254. Next, a modified Horner–Wadsworth– Emmons reaction involving triethylphosphonoacetate (TEPA, 255) was employed to convert epoxide 254 to cyclopropane 256. The reaction presumably proceeds through removal of the acidic TEPA proton followed by nucleophilic attack at the terminal epoxide carbon. The resulting alkoxide undergoes an intramolecular phosphoryl transfer reaction resulting in an enolate, which then attacked the newly formed phosphonate ester in an SN2 fashion resulting in the trans-cyclopropane ester, which was ultimately saponified and re-acidified to furnish cyclopropane acid 256. Conversion of this acid to the corresponding primary amide preceded carbonyl reduction with sodium borohydride. The resulting amine was acylated with propionyl chloride to furnish tasimelteon (XXXI) as the final product in 86% yield across the four-step sequence.

InChI:InChI=1/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1

Upstream product

• 230642-84-9 4-ethenyl-2,3-dihydro-1-benzofuran 
• 364380-03-0 2-chloro-1-(2,3-dihydrobenzofuran-4-yl)ethane-1-one 
• 209257-15-8 trans-(2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methanamine 
• 4122-52-5 1-(1H-imidazol-1-yl)propan-1-one 
• 209257-15-8 1-[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methanamine 
• 79-03-8 propionyl chloride 
• 123-62-6 propionic acid anhydride 
• 1161417-63-5 (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropane-1-carboxamide 

Relevant articles and documents

Development of Jacobsen Asymmetric Epoxidation and Sharpless Asymmetric Dihydroxylation Methods for the Large-Scale Preparation of a Chiral Dihydrobenzofuran Epoxide

Two well-known methodologies, the Jacobsen asymmetric epoxidation (AE) and the Sharpless asymmetric dihydroxylation (AD) followed by epoxidation, were evaluated for the large-scale preparation of a chiral dihydrobenzofuran epoxide. The AE method was improved by substituting ethanol for dichloromethane for the dissolution of meta-chloroperbenzoic acid (m-CPBA). This change in solvent had a significant impact on scaleability of the AE procedure by preventing crystallization of the m-CPBA during addition to the cold reaction mixture. Factors affecting the enantiomeric excess and yield of the chiral epoxide resulting from AD followed by epoxidation were studied. The Sharpless AD reaction provided the intermediate chiral diol as a solid with high ee (>98.5%). The Sharpless-Kolb conversion of the chiral diol to a chiral epoxide was modified to potassium tert-butoxide/tetrahydrofuran to obtain the product in good yield (74-84%) and high ee (>98%). Both the AE and AD processes were scaled up to prepare large quantities of the chiral epoxide.

Preparation method of tasimelteon

The invention provides a preparation method of tasimelteon. The preparation method at least comprises the following steps: carrying out substitution reaction or sulfonation reaction on a compound to obtain a compound III; then reacting the compound III with a propionamide derivative under the condition of an alkaline substance to obtain a tasimelteon derivative compound II; and finally, removing derivative groups from the compound II to obtain tasimelteon. The method has the advantages of short route, high yield, high purity, low overall cost and simple process operation, and is suitable for industrial production, and reagents used in the method are common reagents.

An efficient and practical asymmetric synthesis of (?)-tasimelteon

Tasimelteon is a useful drug for the treatment of Non-24 in totally blind individuals. An efficient and convenient asymmetric synthesis of tasimelteon has been developed from 4-vinyl-2,3-dihydrobenzofuran through six steps in 53% overall yield using the Corey–Bakshi–Shibata (CBS0 asymmetric reduction of ketone as a key step.

Total synthesis of Tasimelteon

A simple and efficient approach has been accomplished for the total synthesis of active pharmaceutical ingredient (API) of Tasimelteon which is effective for treatment of non-24-h sleep-wake disorder. Starting from 4-vinyl-2, 3-dihydrobenzofuran, the synthesis involves asymmetric epoxidation, Wittig reaction, reduction of the nitrile group and propionation of the amine. The synthesis was accomplished in four steps in overall 48% yield.

PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED DIHYDROBENZOFURANS AND INTERMEDIATE COMPOUNDS OBTAINED IN THE PROCESS

It is described an industrially viable and advantageous process for the preparation of (N- (((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide, compound having the formula depicted below and generally known as Tasimelteon, or of intermediates useful in the synthesis thereof: The invention also relates to salts obtained as intermediates of the process.

Processes for the Preparation of Tasimelteon and Intermediates Thereof

The present invention provides processes for the preparation of Tasimelteon (1), as well as processes for the preparation of intermediates of Formulas (2), (3) and (4) useful in the preparation of Tasimelteon (1).

Preparation method of tasimelteon

The invention provides a preparation method of tasimelteon. The preparation method comprises that (S)-4-(oxiranyl-2-yl)-2, 3-dihydrobenzofuran as a starting material undergoes a cyanation reaction to produce (1R, 2R)-2-(2, 3-dihydrobenzofuran-4-yl)cyclopropylcarbonitrile, the (1R, 2R)-2-(2, 3-dihydrobenzofuran-4-yl)cyclopropylcarbonitrile is reduced into ((1R, 2R)-2-(2, 3-dihydrobenzofuran-4-yl)cyclopropyl)methylamine, and the ((1R, 2R)-2-(2, 3-dihydrobenzofuran-4-yl)cyclopropyl)methylamine undergoes an acylation reaction to produce tasimelteon. The method has the advantages of less reaction processes, simple operation, simple after-treatment, high product yield, low raw material cost, industrial production feasibility and large application value.

Synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde

The invention relates to a synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde. The formula of 2,3-dihydro-1-benzofuran-4-carbaldehyde can be shown in the formula (I). The synthesis method comprises the steps of making a compound shown in the formula (II) be subjected to intramolecular cyclization reaction so as to produce a compound shown in the formula (III) under the existence of alkali metal compounds and Cu(1); making the compound shown in the formula (III) be subjected to reaction together with magnesium and a compound shown in the formula R3CONR1R2(IV) so as to obtain the compound shown in the formula (I). According to the synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde, reaction conditions are mild, procedures are simple, byproducts are few, and thus the synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde is suitable for being applied to large scale industrial production.

An optical pure he si Meiqiong preparation method (by machine translation)

The invention provides a method for synthesis of he si Meiqiong, the synthetic method is: shown in formula I raceme transform - [2 - (2, 3 - dihydro - 4 - benzofuryl) cyclopropyl] methylamine, optically pure splitting agent is soluble in the solvent A, in 0 - 70 °C stirring for 2 - 5 hours, the resulting reaction mixture after treatment shown in formula II (1R, 2R) - [2 - (2, 3 - dihydro - 4 - benzofuryl) cyclopropyl] methylamine; dissolving it in the solvent B, add triethylamine, under the protection of nitrogen into the propionyl chloride, in 25 °C stirring reaction under 1 - 2h, the resulting reaction solution after treatment of formula III shown in optical pure he si Meiqiong. The invention has mild reaction condition, the operation is simple, high yield, low production cost, the quality of the product is good, is suitable for industrial production, and has great practical value and social and economic benefits. (by machine translation)

A facile and practical synthesis of (-)-tasimelteon

An efficient and practical route for the synthesis of (-)-tasimelteon from 2,3-bis(2-hydroxyethyl)phenol has been developed. The product was prepared in seven steps in overall 16.4% yield using highly stereoselective cyclopropanation reaction of the intermediate as the key step.