609799-22-6

Tasimelteon, which is marketed by Vanda Pharmaceuticals as Hetlioz and developed in partnership with Bristol-Myers Squibb, is a drug that was approved by the US FDA in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD). Tasimelteon is a melatonin MT1 and MT2 receptor agonist; because it exhibits a greater affinity to the MT2 receptor than MT1, is also known as Dual Melatonin Receptor Agonist.234 Two randomized controlled trials (phases II and III) demonstrated that tasimelteon improved sleep latency and maintenance of sleep with a shift in circadian rhythms, and therefore has the potential to treat patients with transient insomnia associated with circadian rhythm sleep disorders. Preclinical studies showed that the drug has similar phase-shifting properties to melatonin, but with less vasoconstrictive effects.

Tasimelteon is a novel drug, used in the treatment of non-24 hour sleep-wake disorder. It helps to correct the circadian rhythm disorder often seen in patients who are visually impaired.

ChEBI: A member of the class of 1-benzofurans that is propionamide in which one of the amide hydrogens is replaced by a [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl group. A melatonin receptor agonist used for the treatment of non-24-hour sleep-wake disorder.

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¨CWadsworth¨C 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.

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