Preparation method of ramelteon intermediate

A technology of ramelteon and intermediates, which is applied in the field of preparation of ramelteon intermediates, can solve the problems of long reaction steps, complicated operation and high cost, and achieves the effects of shortening reaction steps, simple post-processing and avoiding generation.

Inactive Publication Date: 2013-09-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Moreover, this route also uses toxic and irritating phosphine reagents, which are expensive, have long reaction steps, cumbersome operations, low yields, and high costs, and are not suitable for industrial production.

Method used

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  • Preparation method of ramelteon intermediate
  • Preparation method of ramelteon intermediate
  • Preparation method of ramelteon intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of (E)-2-(4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile (IV)

[0025] 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (II) (33.20g, 0.100mol), cyanoacetic acid (III ) (21.30g, 0.250mol), benzylamine (2.68g, 0.025mol) and heptanoic acid (3.38g, 0.026mol) were added to toluene (300ml), heated to reflux. After the reaction of (II) was complete, cooling and crystallization gave 30.10 g of solid (IV) with a yield of 87.3%.

[0026] 1 H-NMR (CDCl 3 , 300MHz): δ6.68(1H, m), δ4.76(2H, t, J=17.5Hz), δ3.61(2H, d), δ3.53(2H, t, J=17.5Hz), δ3.40(2H,d).

Embodiment 2

[0028] Preparation of (E)-2-(4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile (IV)

[0029] 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (II) (16.60g, 0.050mol), cyanoacetic acid (III ) (12.75g, 0.150mol), phenethylamine (1.82g, 0.015mol) and added to toluene (135ml), heated to reflux. After the reaction of (II) was complete, cooling and crystallization gave 14.66 g of solid (IV), with a yield of 82.6%.

Embodiment 3

[0031] Preparation of 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (I)

[0032] (IV) (28.4g, 0.080mol), sodium acetate (16.4g, 0.200mol), 10% palladium carbon (2.84g) and ethanol solution (580ml) are added in the autoclave, lead hydrogen to 4MPa, then be heated to 40 ° C, stirring for 8h. Filtrate, add Raney nickel (14.2g) and ammonia water (65ml) to the filtrate, pass hydrogen to 4MPa, heat to 40°C and stir for 4h. Filtrate, distill off the filtrate under reduced pressure to obtain a light yellow oil, add water (50ml) and ethyl acetate (150ml) and stir to dissolve, separate the ethyl acetate layer, dry over anhydrous sodium sulfate, filter, pass hydrogen chloride gas into the filtrate, Precipitation occurred. Filtration, the precipitate was washed with ethyl acetate and dried to obtain off-white solid 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride Salt (I) 14.5g, yield 75.6%.

[0033] 1 H-NMR (DMSO, 300MHz): δ1.55-1...

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Abstract

The invention discloses a novel preparation method of a ramelteon intermediate 2-(1, 2, 6, 7-tetrahydro-8H-indeno[5, 4-b] furan-8-yl) ethylamine hydrochloride (I). The method is characterized by comprising the following steps: dehydrating and condensing and heating and decarboxylating 4, 5-dibromo-1, 2, 6, 7-tetrahydro-8H-indeno[5, 4-b] furan-8-one (II) and cyanoacetic acid (III) under the effect of a catalyst to obtain a compound (IV); then, hydrogenating the (IV) and salifying to obtain the ramelteon intermediate hydrochloride (I). The invention provides a novel preparation of the ramelteon intermediate hydrochloride (I). According to the method, cyanoacetic acid (II) which is cheap and easily available is used, so that the method is simplified in synthetic step, high in efficiency and simple and convenient to operate, and the method is a preparation method which is more suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of ramelteon intermediate. Background technique [0002] Ramelteon (ramelteon), chemical name (S)-N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)]propane Amide, the structural formula is as follows: [0003] [0004] Developed by Japan's Takeda Corporation, in September 2005, it was approved by the US FDA for marketing. It is the first melatonin receptor agonist used in clinical treatment of insomnia, it can selectively stimulate melatonin type 1 receptor and type 2 receptor (MT 1 , MT 2 ), which is mainly used to treat insomnia with difficulty falling asleep, and also has definite curative effect on chronic insomnia and short-term insomnia. [0005] The key to the currently reported synthesis route of ramelteon is to construct the chiral center in the molecule. At present, there are two main methods: one is to synthesize by asymmetric ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
Inventor 陈国华姚世伦滕海堂赵方露谢吴辰
Owner CHINA PHARM UNIV
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