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Compound for preparing ramelteon, preparation method thereof and application thereof

A compound and condensation reaction technology, which is applied in the field of preparation of ramelteon, a drug for treating insomnia, can solve the problems of unavailable, high raw material prices, harsh reaction conditions, etc.

Inactive Publication Date: 2010-02-24
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The above-mentioned method for synthesizing optically active ramelteon has higher raw material prices and is not easy to obtain (such as: [RuCl(benzene)(R)-BINAP]Cl, Ru(OAc) 2 -[(R)-BINAP], Ru 2 Cl 4 [(R)-BINAP] 2 NET 3 , amidohydrolase, etc.); the reaction conditions are harsh (requires absolute anhydrous solvent, high-pressure hydrogenation); there are many reaction steps and the total yield is low; the "three wastes" are seriously discharged during the preparation process; Insufficiencies such as excessive heavy metals make the preparation cost of ramelteon higher, and the large-scale preparation is limited

Method used

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  • Compound for preparing ramelteon, preparation method thereof and application thereof
  • Compound for preparing ramelteon, preparation method thereof and application thereof
  • Compound for preparing ramelteon, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Preparation of (1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)acetonitrile (2)

[0061] Add 21.27 g (0.12 mol) of diethyl cyanomethylene phosphonate, 1,2,6,7-tetrahydro-8H-indeno-[5,4-b]furan-8-one in sequence in the reaction flask 17.42g (0.10mol), 120ml of toluene and 60ml of deionized water, after stirring at room temperature, add 1.62g (0.005mol) of tetrabutylammonium bromide and 20.70g (0.15mol) of anhydrous potassium carbonate, and heat up to 60-70 ℃, keep stirring and react for 8 hours; after the reaction, cool to room temperature, separate the toluene layer, extract the water layer with 30ml of toluene, combine the toluene solution, wash with 25ml of saturated NaCl aqueous solution, evaporate the solvent under reduced pressure, and recrystallize the residue with methanol , to obtain 17.20 g of light yellow crystalline solid, mp: 146-148°C, yield 87.2%.

Embodiment 2

[0063] Preparation of (1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)acetonitrile (2)

[0064] Add 40.54 g (0.12 mol) of cyanomethylenetriphenylphosphonium chloride, 1,2,6,7-tetrahydro-8H-indeno-[5,4-b]furan-8- Ketone 17.42g (0.10mol) and toluene 200ml, after stirring at room temperature evenly, put in an ice bath and cool to 0-5°C, add 15% sodium methoxide methanol solution (0.13mol) dropwise, remove the ice bath, and stir at room temperature React for 2.5h, add 100ml of deionized water to the reaction bottle, stir for 30min, pour the reaction solution into a separatory funnel, separate the organic layer, and wash with 40ml of saturated aqueous NaCl solution, evaporate the solvent under reduced pressure, and reconstitute the residue with methanol Crystallized to obtain 16.51 g of light yellow crystalline solid, mp: 145-148°C, yield 83.7%.

Embodiment 3

[0066] Preparation of methyl (1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)acetate (3a)

[0067] The operation process is the same as in Example 1, except that diethyl cyanomethylene phosphonate is replaced with 2-(diethoxyphosphonic acid group) methyl acetate to obtain (1,6,7,8-tetrahydro-2H-indene And-[5,4-b]furan-8-ylidene)acetate methyl ester as light yellow oily liquid, yield 92.1%. It was directly used in the next reaction without further purification.

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Abstract

The invention discloses 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) acetic acid(I) and an optical isomer(II) thereof; and the invention also discloses a method for preparing the compound and the application of the compound in the preparation of ramelteon which is a medicament for treating insomnia.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetic acid (I), optical isomers ( II), its preparation method and its application in the preparation of insomnia treatment medicine—Ramelteon (Ramelteon) medicine. [0002] Background technique [0003] The chemical name of ramelteon is: (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl] Propionamide, a potent and highly selective melatonin receptor agonist, binds to melatonin MT on the suprachiasmatic nucleus (also known as the circadian clock) 1 and MT 2 The receptor has a higher affinity than the MT 3 Receptor effects; ramelteon on MT 1 and MT 2 Receptors are fully agonistic and specific to MT 1 The affinity and selectivity of the receptor are stronger than melatonin, while MT 1 The receptor is considered an integral part of the body's sleep regulation, and unlike benzodiazepines, this product does not re...

Claims

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Application Information

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IPC IPC(8): C07D307/93A61K31/343A61P25/20
CPCY02P20/582
Inventor 邓勇李梅沈怡钟裕国
Owner SICHUAN UNIV
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