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Preparation method of high-purity ramelteon

A ramelteon, high-purity technology, applied in the field of preparation of high-purity ramelteon, can solve the problems of affecting the total yield of the process and product quality, increasing production costs, difficulties, etc., to achieve the suppression of the formation of impurity VIII, Reduced purification pressure and high reaction yield

Active Publication Date: 2017-04-26
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is worth noting that these three preparation methods will form impurity VIII in the product; however, it is difficult to effectively remove impurity VIII through the subsequent refining of the product, and multiple refining (4 to 5 times of refining) are required.
In addition, impurity Ⅷ seriously affects the total yield and product quality of the process, while increasing the production cost

Method used

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  • Preparation method of high-purity ramelteon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Add tetrahydrofuran (22L) and 60% NaH (2kg) into a 50L double-layer glass reactor and stir evenly below 25°C. Diethyl cyanomethylphosphonate (14kg) was added dropwise and stirred for 1 hour to obtain a clear ylide solution. Add tetrahydrofuran (22L) and 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone (formula (I) compound) in addition in 100L double-layer glass reaction kettle ( 4kg) and stir evenly. Add the freshly prepared ylide solution dropwise into the system, stir and react for 3 hours, then slowly add water (22 L) into the reaction system, and continue stirring for 30 minutes after the addition is complete. The reaction solution was poured into water (202 L) and stirred for 1 hour. Filtration gave 5.1 kg of 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylideneacetonitrile (compound of formula (II)).

[0046] Add formula (II) compound (5kg), absolute ethanol (74L) and di-tert-butyl dicarbonate (11kg) in 300L glass-lined reaction tank and stir evenly, add sodium b...

Embodiment 2

[0052] Add tetrahydrofuran (22L) and 60% NaH (2kg) into a 50L double-layer glass reactor and stir evenly below 25°C. Diethyl cyanomethylphosphonate (14kg) was added dropwise and stirred for 1 hour to obtain a clear ylide solution. Add tetrahydrofuran (22L) and 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone (formula (I) compound) in addition in 100L double-layer glass reaction kettle ( 4kg) and stir evenly. Add the freshly prepared ylide solution dropwise into the system, stir and react for 3 hours, then slowly add water (22 L) into the reaction system, and continue stirring for 30 minutes after the addition is complete. The reaction solution was poured into water (202 L) and stirred for 1 hour. Filtration gave 5.1 kg of 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylideneacetonitrile (compound of formula (II)).

[0053] Add formula (II) compound (5kg), absolute ethanol (74L) and di-tert-butyl dicarbonate (11kg) in 300L glass-lined reaction tank and stir evenly, add sodium ...

Embodiment 3

[0059] Add tetrahydrofuran (22L) and 60% NaH (2kg) into a 50L double-layer glass reactor and stir evenly below 25°C. Diethyl cyanomethylphosphonate (14kg) was added dropwise and stirred for 1 hour to obtain a clear ylide solution. Add tetrahydrofuran (22L) and 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone (formula (I) compound) in addition in 100L double-layer glass reaction kettle ( 4kg) and stir evenly. Add the freshly prepared ylide solution dropwise into the system, stir and react for 3 hours, then slowly add water (22 L) into the reaction system, and continue stirring for 30 minutes after the addition is complete. The reaction solution was poured into water (202 L) and stirred for 1 hour. After filtration, 5.1 kg of 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylideneacetonitrile (compound of formula (II)) was obtained.

[0060] Add formula (II) compound (5kg), absolute ethanol (74L) and di-tert-butyl dicarbonate (11kg) in 300L glass-lined reaction tank and stir even...

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PUM

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Abstract

The invention discloses a preparation method of high-purity ramelteon. The preparation method comprises the following steps: taking 1,2,6,7-tetrahydro-8H-indene[5,4-b]furan-8-ketone as a starting material; carrying out reduction and amino protection through wittig-horner reaction; carrying out amino deprotection under an acidic condition; carrying out hydrogenation reaction; then carrying out chiral resolution and acrylation reaction, thus obtaining the ramelteon. The ramelteon obtained through the invention is high in product purity and higher in yield; and formation of impurities is inhibited.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of high-purity ramelteon, wherein the formation of impurities is suppressed. Background technique [0002] Ramelteon, chemical name (S)-N-(2-(1,6,7,8-tetrahydro-2H-indeno(5,4-b)furan-8-yl)ethyl)propane Amide, a melatonin receptor agonist developed by Takeda Corporation of Japan, can selectively act on MT1 and MT2 receptors. It was approved by the US FDA in 2005 for the treatment of insomnia characterized by difficulty falling asleep. Ramelteon has no affinity for GABA receptors, acetylcholine receptors, and opioid receptors. It has a completely different mechanism of action from traditional sedative-hypnotics, and has a long acting time and few adverse reactions. Obviously addictive, it is the first sedative-hypnotics listed as special control. [0003] The main structure of ramelteon is the indenofuryl ethylamine part, followed by the propion...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
Inventor 张杰李国贤罗宏军朱晓鹤薛涛胡涛陈令武
Owner YANGTZE RIVER PHARM GRP CO LTD
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