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2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation

A technology of 4-b and furan, which is applied in the field of preparation of ramelteon, a drug for treating insomnia, can solve the problems of high raw material prices, difficult availability, and cumbersome post-processing processes, etc.

Inactive Publication Date: 2010-09-08
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] 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 synthesis cost of ramelteon higher, the purity is on the low side, and the large-scale preparation is limited

Method used

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  • 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation
  • 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation
  • 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Preparation of (S)-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetamide (S-2)

[0058] 10.92 g (0.05 mol) of (S)-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetic acid, 8.93 g (0.075 mol) of thionyl chloride and a catalytic amount of N,N-dimethylformamide were heated and refluxed for 1.5 hours with stirring. After the reaction, the excess thionyl chloride was evaporated under reduced pressure, and the residue was added 80ml of anhydrous tetrahydrofuran, after stirring evenly, slowly add this solution dropwise into 40ml of ice-cold concentrated ammonia water, stir at room temperature for 3h, distill off tetrahydrofuran under reduced pressure, filter, and recrystallize the obtained crude product with ethanol to obtain (S)-2-( 9.94 g of white needle-like crystals of 1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetamide, mp: 214-216°C, yield 91.5% , 1 H NMR (DMSO-d 6 , 400MHz) δ: 7.35 (brs, 1H, NH), 6.90 (d, J=8.0Hz, 1H, Ar-H), 6.84 (brs, 1H, NH), 6.52...

Embodiment 2

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

[0061] The operation process is the same as in Example 1, except that (S)-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetic acid is used in (R) -2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetic acid was substituted to give (R)-2-(1,6,7, White needle-like crystals of 8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetamide, mp: 213~215°C, yield 85.9%,

Embodiment 3

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

[0064] (S)-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)acetic acid 10.92g (0.05mol), triethylamine 6.10g (0.06mol) and 50ml of dichloromethane were added to the reaction flask, cooled in an ice bath, 6.51g (0.06mol) of ethyl chloroformate was added dropwise, stirred at room temperature for 5.0h, and then the mixture was slowly added dropwise to ice-cold In 30ml of concentrated ammonia water, stirred at room temperature for 3h, dichloromethane was distilled off under reduced pressure, filtered, and the obtained crude product was recrystallized with ethanol to obtain (S)-2-(1,6,7,8-tetrahydro-2H-indeno 8.92 g of white needle crystals of -[5,4-b]furan-8-yl)acetamide, mp: 214-216°C, yield 82.1%.

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Abstract

The invention discloses 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile (I), an optical isomer (II) thereof, a preparation method of the compound and application of the compound in preparing 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)acetonitrile (I) and its optical isomers (II), and its preparation method and its application in the preparation of insomnia treatment medicine—Ramelteon (Ramelteon) medicine. [0002] Background technique [0003] Ramelteon is a tricyclic synthetic analog of melatonin with the chemical name: (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4 -b]furan-8-yl)ethyl]propionamide, the first melatonin receptor agonist approved by the FDA. It interacts with 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 function, while MT 1 The receptors are considered an integral part of the body's sleep regulation. 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77A61K31/343A61P25/20
Inventor 邓勇李梅沈怡钟裕国
Owner SICHUAN UNIV
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