196597-26-9 Usage
Description
Ramelteon is a synthetic melatonin receptor agonist that has been specifically designed to target the melatonin MT1 and MT2 receptors. It is structurally different from melatonin, with modifications to the indole ring and the incorporation of a 5-methoxyl group into a more rigid furan ring. Ramelteon exhibits high selectivity for the MT1 receptor, which is primarily involved in initiating sleep, and has a lower affinity for the MT2 receptor, which is associated with the regulation of circadian rhythms. Unlike traditional hypnotic drugs, ramelteon does not interact with the GABA receptor complex or other neurotransmitter receptors, resulting in a better safety profile and no addiction liability. It is available under the brand name Rozerem and is approved for the treatment of insomnia.
Uses
1. Used in Pharmaceutical Industry:
Ramelteon is used as a sedative and hypnotic agent for the treatment of insomnia. It works by selectively targeting the melatonin MT1 and MT2 receptors, promoting sleep onset and improving sleep quality without the risk of addiction or abuse potential.
2. Used in Sleep Aid Applications:
Ramelteon is used as a sleep aid for individuals experiencing difficulty falling asleep or maintaining sleep. Its high selectivity for the MT1 receptor makes it more effective in initiating sleep compared to melatonin, while its lower affinity for the MT2 receptor reduces the potential for disrupting circadian rhythms.
3. Used in Insomnia Treatment:
Ramelteon is used in the treatment of insomnia, particularly for patients who have difficulty falling asleep or staying asleep throughout the night. Its unique mechanism of action, targeting the melatonin receptors without interacting with other neurotransmitter systems, offers a safer alternative to traditional hypnotic drugs.
4. Used in Non-Addictive Sleep Medication:
Ramelteon is used as a non-addictive sleep medication, providing relief from insomnia without the risk of developing a dependency or experiencing withdrawal symptoms. Its lack of interaction with the GABA receptor complex and other neurotransmitter systems contributes to its improved safety profile.
5. Used in Circadian Rhythm Regulation:
Ramelteon is used to help regulate circadian rhythms in individuals with insomnia, as it has a lower affinity for the MT2 receptor compared to the MT1 receptor. This selective targeting allows for improved sleep quality without significantly disrupting the body's natural circadian rhythm.
Originator
Takeda (Japan)
Synthesis
Vilsmeier-Haack reaction on benzofuran 112 provided
aldehyde 113 (100%), which was converted to olefin 114
(88%) by Horner-Emmons reaction with triethylphosphonoacetate,
and was followed by hydrogenation of the olefin to
give ester 115 (100%). In order to avoid the cyclization of
the acid chloride intermediate into the wrong position, the
benzene ring was protected by bromination. Both bromination
and hydrolysis of the ester is accomplished in a single
pot to give acid 116. Thus the ester is brominated with bromine
in sodium acetate and acetic acid at 0°C and RT for several hours followed by quenching of remaining bromide
by sodium thiosulfate. The resulting acidic solution was
taken up in acetonitrile and refluxed for 2hr to provide the
acid 116 in 73% yield. The conversion of the acid to acid
chloride was done by reacting with thionyl chloride in odichlorobenzene
at 40°C for 30 to 40 min after which the
reaction was cooled to 0°C . Aluminum trichloride was
added and the reaction mixture was stirred at 0°C for 30 min
to deliver cyclized ketone 117 in 92% yield. After completion
of the cyclization, the bromines are removed by hydrogenation
(86%) and resulting ketone 118 was then reacted
under Horner-Emmons condition with diethyl cyano phosphonate
to give vinyl nitrile 119 in 84% yield. Selective reduction
of the nitrile was accomplished by hydrogenation
under basic condition (sodium hydroxide in toluene) in the presence of the activated cobalt at 25-50°C for 6.5 hr. The
amine was recovered as hydrochloride salt 120 (99% yield)
by treating the amine with HCl in methanol. In the next step,
the amine salt 120 was taken up in toluene and treated with
sodium hydroxide followed by hydrogenation of the mixture
with [RuCl(benzene)(R)-BINAP]Cl as catalyst to provide
chiral amine 121, after several work up and palladium catalyzed
hydrogenations, in 73% overall yield. Final acylation
of the amine with propionyl chloride in the presence of
aqueous sodium hydroxide in THF at room temperature gave
the desired product ramelteon (XVI), after crystallization, in
97% yield.
references
[1] miyamoto m. pharmacology of ramelteon, a selective mt1/mt2 receptor agonist: a novel therapeutic drug for sleep disorders. cns neurosci ther. 2009 winter;15(1):32-51. doi: 10.1111/j.1755-5949.2008.00066.x.
Check Digit Verification of cas no
The CAS Registry Mumber 196597-26-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,9,6,5,9 and 7 respectively; the second part has 2 digits, 2 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 196597-26:
(8*1)+(7*9)+(6*6)+(5*5)+(4*9)+(3*7)+(2*2)+(1*6)=199
199 % 10 = 9
So 196597-26-9 is a valid CAS Registry Number.
InChI:InChI=1/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m0/s1
196597-26-9Relevant articles and documents
Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis
?asar, Zdenko,Cluzeau, Jér?me,Kova?evi?, Miroslav Planinc,Nettekoven, Ulrike
supporting information, (2021/10/20)
A concise six-step asymmetric synthesis of nearly enantiomerically pure ramelteon was developed from a monocyclic precursor with a 17% overall yield and a 97% ee in the asymmetric step. The synthetically challenging tricyclic 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan core of ramelteon was assembled by using Ir-catalyzed O-vinylation and Rh-catalyzed vinyl ether annulation through directed C-H bond activation, while the chirality was introduced with enantioselective reduction of an α,β-unsaturated nitrile moiety under hydrosilylation conditions using a CuII/Walphos type catalyst. The presented methodology represents the shortest synthetic approach to ramelteon.
A process for the preparation of key intermediate lei meiti amine, its preparation and use
-
, (2020/02/07)
The invention discloses critical intermediates (with the structure formula (I) ) used for preparing ramelteon. In the formula (I), A is O or S; R is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, phenyl, benzyl or p-methoxybenzyl; and when chiral carbon exists, the chemical compounds in the formula (I) are racemate or optically active compounds. When the A in the formula (I) is O and the R in the formula (I) is ethyl, the chemical compound is the chemical compound shown as the structure formula (II). In addition, the invention further discloses a preparing method of the chemical compound shown as the formula (II) and applications of the formula (II) in preparation of the ramelteon used for treating insomnia.
A lightning-US for amine method for the preparation of (by machine translation)
-
, (2017/05/18)
The invention relates to a preparation method of Ramelteon. The method mainly comprises three reaction steps of hydrogenation, chiral resolution and acylation reaction. According to the synthesis of the Ramelteon, 2-(1,6,7,8-tetralin-2H-indeno[5,4-b]furan-8-subunit) ethylamine hydrochloride serves as a start raw material, Pd-C serves as a catalyst, and 2-(1,6,7,8-tetralin-2H-indeno[5,4-b]furan-8-base) ethylamine hydrochloride, namely an midbody-1, is acquired through catalytic hydrogenation; chiral resolution is conducted on the midbody-1 through dibenzoyl-L-tartrate, so that (S)-2-(1,6,7,8-tetralin-2H-indeno[5,4-b]furan-8-base) ethylamine dibenzoyl-L-tartrate, namely a midbody-2, is acquired; an acylation reaction is conducted on the midbody-2 and propionyl chloride, so that a crude product of the Ramelteon is acquired, and a finished product of the Ramelteon is acquired after the crude product is refined and qualified.
