Nedemelteon

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Nedemelteon

CAS 1000334-38-2

MF C15H18N2O2 MW258.32

N-[2-[(8S)-2-methyl-7,8-dihydro-6H-cyclopenta[g][1,3]benzoxazol-8-yl]ethyl]acetamide

N-{2-[(8S)-2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl}acetamide
melatonin receptor agonist, CW62HV1TTF, MT1/2 Agonist (S)-3b

Nedemelteon is a melatonin receptor agonist.

Nedemelteon is a small molecule drug. The usage of the INN stem ‘-melteon’ in the name indicates that Nedemelteon is a melatonin receptor agonist. Nedemelteon has a monoisotopic molecular weight of 258.14 Da.

SYN

Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2021-03-08

PMID: 33682410

DOI: 10.1021/acs.jmedchem.0c01836

SYN

US8552037,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US76841372&_cid=P22-MLU9PK-87296-1

EXAMPLE 11

N-[2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide

N-[2-(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide (165 mg, 0.644 mmol) was dissolved in methanol (6.4 mL), a 10% palladium-carbon powder (82 mg) was added, and the mixture was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (148 mg, yield 89%).

¹H-NMR (CDCl ₃) δ: 1.69-1.96 (2H, m), 1.99 (3H, s), 2.23-2.50 (2H, m), 2.63 (3H, s), 2.89-3.15 (2H, m), 3.28-3.56 (3H, m), 5.54 (1H, brs), 7.15 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz),

melting point: 93-95° C. (recrystallized from hexane/ethyl acetate),

MS (ESI+): 259 (M+H),

Elemental analysis: for C ₁₅H ₁₈N ₂O ₂

Calcd. (%): C, 69.74; H, 7.02; N, 10.84

Found (%): C, 69.77; H, 6.97; N, 10.95.

EXAMPLE 12

(S)-N-[2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide

Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide (768 mg, 3.00 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 1.02 mg/mL, injection weight: 31 mg). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (381 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.65 mg/mL (hexane/ethanol), injection volume: 10 μL).

¹H-NMR (CDCl ₃) δ: 1.69-1.96 (2H, m), 1.99 (3H, s), 2.23-2.50 (2H, m), 2.63 (3H, s), 2.89-3.15 (2H, m), 3.28-3.56 (3H, m), 5.54 (1H, brs), 7.15 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz),

melting point: 111-113° C. (recrystallized from hexane/ethyl acetate),

MS (ESI+): 259 (M+H),

[α] _D ²⁰: −53.4° (c 0.5035, methanol),

Elemental analysis: for C ₁₅H ₁₈N ₂O ₂

Calcd. (%): C, 69.74; H, 7.02; N, 10.84

Found (%): C, 69.53; H, 7.01; N, 10.96.

SYN

WO-2007148808

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007148808&_cid=P22-MLU9Y2-93563-1

Example 12
(S) -N- [2- (2-Methyl-7, 8-dihydro-6H-indeno [5, 4-d] [1, 3] oxazol-8-yl) ethyl] acetamide

Racemic N- [2- (2-methyl-7, 8-dihydro-6H-indeno [5, 4-d] [1,3] oxazol-8-yl) ethyl] acetamide (768 mg, 3.00 mmol) was fractionated by high performance liquid chromatography
(instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRΔLPAK AD (50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase:
hexane/ethanol/diethylamine=90/10/0.1, flow rate: 60 mL/min, column temperature: 30°C, sample concentration: 1.02 mg/mL, injection weight: 31 mg) . A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (381 mg, 99.9%ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID x 250 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 0.5 mL/min, column temperature: 30⁰C, sample concentration:

0.65 mg/mL (hexane/ethanol) , injection volume: 10 μL) .
¹H-NMR (CDCl₃) δ: 1.69 – 1.96 (2H, m) , 1.99 (3H, s) , 2.23 – 2.50 (2H, m) , 2.63 (3H, s) , 2.89 – 3.15 (2H, m) , 3.28 – 3.56 (3H, m) ,

5.54 (IH, brs), 7.15 (IH, d, J = 8.0 Hz), 7.44 (IH, d, J = 8.0Hz),
melting point: 111 – 113°C (recrystallized from hexane/ethyl acetate) ,
MS (ESI+) : 259 (M+H) ,
[α] _D²⁰: -53.4° (c 0.5035, methanol),
Elemental analysis: for Ci₅Hi₈N₂O₂
Calcd. (%) : C, 69.74; H, 7.02; N, 10.84
Found (%) : C, 69.53; H, 7.01; N, 10.96.

PAT