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Preparation method and intermediate of ramelteon

A technology of ramelteon and reaction time, applied in the preparation of ramelteon and the field of intermediates thereof, can solve the problems of being difficult to obtain, unfavorable to meet the quality requirements of industrialized production products, expensive metal complex catalysts, etc. Low cost, guaranteed quality and safety, good product stability

Inactive Publication Date: 2013-02-13
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The metal complex catalyst used in the chiral catalytic reduction reported in this type of patent is expensive, difficult to obtain and not conducive to meeting the quality requirements of industrial production products, and the molar amount of hydrogen used in catalytic hydrogenation reduction is four times that of 2-(1,2, 6,7-tetrahydro-8H-indeno[5,4b]furan-8-ylidene)acetonitrile compound

Method used

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

Examples

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Effect test

Embodiment 1

[0043] Preparation of 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ene)-N-phthalimide

[0044] Add N-(2-triphenylphosphine)phthalimide bromide salt (227g, 0.44mol) and anhydrous tetrahydrofuran (185mL) into the reaction flask, add 60% sodium hydride (19.2g , 0.44mol), after the addition was completed, the reaction was stirred at room temperature for 1h. After the reaction, the above reaction solution was added dropwise into 280 mL tetrahydrofuran solution containing 1,2,6,7-tetrahydro-8H-indeno[5,4b]furan-8-one (70g, 0.4mol), dropwise After completion, react at room temperature until the reaction of the raw material 1,2,6,7-tetrahydro-8H-indeno[5,4b]furan-8-one is complete, add 200mL water to terminate the reaction, and wash the aqueous layer with ethyl acetate (100 mLx3) Extracted, combined organic layers, washed with saturated brine (100 mLx3), dried over anhydrous sodium sulfate, filtered filtrate was evaporated to dryness to obtain 96.5 g of white solid, yield 72.5%.

Embodiment 2

[0046] Preparation of 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)-N-phthalimide

[0047] Add 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ene)-N-phthalimide (53g, 0.4mol), Raney nickel (10g) and saturated ammonia ethanol solution (1L) were added to a 3 L autoclave, hydrogen was introduced to 4MPa, heated to 40°C and stirred for 5 hours, filtered, and the filtrate was evaporated to dryness to obtain Yellow solid 49.4g, yield 92.6%.

Embodiment 3

[0049] Preparation of 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethylamine

[0050] Add 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)-N-phthalimide (43g, 0.13mol) and ethanol (1L), add hydrazine hydrate (19g, 0.39mol) dropwise at room temperature, react at 70°C for 8h after the dropwise addition, filter, wash the colloidal solid with ethyl acetate, collect the filtrate and evaporate to dryness to obtain light yellow Oil (22.5g, 92.1%).

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Abstract

The invention discloses a preparation method and an intermediate of ramelteon. The preparation method comprises the following steps: 1. deprotecting a compound (5) in an organic solvent to obtain a compound (6); 2. after condensing the compound (6) and a chiral resolution reagent, crystallizing to obtain an S type condensate crystal, and hydrolyzing under alkaline conditions to obtain an S type optical isomer compound (7) of the compound (6); and 3. reacting the compound (7) with propionyl chloride under alkaline conditions to generate the ramelteon (8).

Description

technical field [0001] The patent of this invention relates to the drug for the treatment of insomnia - ramelteon ((S)-N-2-[1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8 - a preparation method of ethyl] propionamide), and a class of intermediate (2-(1,6,7,8-tetrahydro-2H-indeno-[5 , 4-b] furan-8-yl) ethylamines) and its application in the preparation of ramelteon. Background technique [0002] Ramelteon, chemical name: (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl ] propionamide, its structural formula is as follows: [0003] [0004] Ramelteon is a new molecular drug developed by Japan's Takeda Corporation (TAKEDA) for the treatment of insomnia with difficulty falling asleep, chronic insomnia and short-term insomnia. It was launched in Japan in 2008 under the product name: ロゼレム?; it was launched in the United States in 2005 under the product name: ROZEREM. melatonin receptor agonists. [0005] The currently reported strategies for constructing chiral c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77C07D405/06
CPCY02P20/55
Inventor 宋波邹江杨琰
Owner CHINA RESOURCES SAIKE PHARMA
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