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Novel method for preparing ramelteon key intermediate

A technology for ramelteon and intermediates, applied in the field of chemical and pharmaceutical industries, can solve the problems of low yield and achieve the effects of simple post-treatment, mild reaction conditions and high yield

Inactive Publication Date: 2012-05-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above methods all use toxic or irritating phosphine reagents, and the yield is not high

Method used

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  • Novel method for preparing ramelteon key intermediate
  • Novel method for preparing ramelteon key intermediate
  • Novel method for preparing ramelteon key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0026] Example: 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (I)

[0027] step 1):

[0028] 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (II) (34.8g, 0.200mol), cyanoacetic acid (III) (25.5g, 0.300mol ) and piperidine (0.084g, 0.986mmol) were added to toluene (160ml), stirred, and heated to reflux. After the reaction of compound (II) is complete, filter, concentrate the solvent under reduced pressure, add water (140ml), extract with ethyl acetate (50ml×3), wash with saturated aqueous sodium chloride until neutral, concentrate the solvent under reduced pressure to obtain a solid compound (IV) (36.4 g, 92.4%).

[0029] Melting point: 144-147°C

[0030] Step (2):

[0031] Add compound (IV) (34.5g, 0.175mol), Raney nickel (6.9g) and ammonia-saturated ethanol solution (800ml) into a 2L autoclave, and feed hydrogen to 40kg / m 2 , heated to 40 ° C, stirred for 5h. Filter, add 10% palladium carbon (3.6g) to the filtrate, pass hydrogen to 40kg / m 2 ...

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Abstract

The invention discloses a novel method for preparing a ramelteon key 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 of: performing dehydration condensation and heated decarboxylation on 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (II) and cyanoacetic acid (III) under the action of a catalyst to obtain a compound (IV); and directly hydrogenating and salifying the compound (IV) without separating and purifying to obtain the ramelteon key intermediate 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (I). The invention provides the novel method for preparing the ramelteon key intermediate hydrochloride (I). In the method, the cheap and readily available cyanoacetic acid (II) is used; and the method is high in yield and low in cost, is easy and convenient to operate, is environment-friendly and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and pharmacy, and relates to a new preparation method of ramelteon key intermediate hydrochloride. technical background [0002] Ramelteon (ramelteon), chemical name (S)-N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)]propane Amide, with the following structural formula, was developed by Japan's Takeda Company and was approved by the US FDA in September 2005. It is a new type of melatonin receptor agonist, which can selectively stimulate melatonin type 1 receptor and type 2 receptor (MT1, MT2), increase slow wave sleep (SWS) and rapid eye movement sleep (REW) , which helps to regulate the sleep cycle and improve sleep quality, is the first non-addictive insomnia drug that is not under special control. [0003] [0004] Ramelteon [0005] 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride is a key intermediate for the synthesis of ramelteon, its structura...

Claims

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Application Information

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IPC IPC(8): C07D307/93
Inventor 陈国华江传亮钟永刚潘瑜群李昂
Owner CHINA PHARM UNIV
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