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Resolution method of ramelteon intermediate

A technology for ramelteon and intermediates, applied in the field of resolution of ramelteon intermediates, can solve the problems of resolution yield and efficiency without detailed results, achieve good application prospects, easy operation, and controllable quality Effect

Inactive Publication Date: 2015-02-04
SUZHOU JONATHAN NEW MATERIALS TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] CN102924410, Chinese Journal of Pharmaceutical Industry 2009,40 (3) 161-164, WO2010 / 55481 announced the use of resolution reagents including: S-ibuprofen, L-(-)-dibenzoyl tartaric acid monohydrate and S- Ibuprofen resolves and synthesizes the racemate, but the first two Chinese documents only provide detailed examples and results of the resolution of L-(-)-dibenzoyltartaric acid monohydrate, and the latter one only provides The resolution of S-ibuprofen gives a brief example without detailed results on the resolution yield and efficiency;

Method used

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  • Resolution method of ramelteon intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Put S-ibuprofen (100g, 0.487mol, 1eq) and acetonitrile (1L) into the reaction flask, stir to dissolve it, and add 2,2-(1,6,7,8-tetrahydro-2H -Indeno[5,4-B]furan-8-yl)ethylamine (100g, 0.487mol, 1eq) in methanol (0.5L) solution, kept dropping within 30 minutes, after dropping, refluxed and stirred for two hours, Naturally cooled to room temperature, stirred at 0-5 degrees Celsius for 5 hours, filtered, and the filter cake was placed in a mixed solvent of acetonitrile and methanol (1L, v:v=6:4), heated at 80 degrees Celsius to dissolve it completely, and cooled naturally After crystallization, stir at 0-5 degrees Celsius for 5 hours, filter, add 1M aqueous sodium hydroxide solution to the filter cake to adjust the pH=10-12, stir for 15 minutes, filter, wash the filtrate to nearly neutral, and dry at 50 degrees Celsius to obtain White solid 35g, yield: 70%, ee: 97%.

Embodiment 2

[0022] Put S-ibuprofen (100g, 0.487mol, 1eq) and ethyl acetate (1L) into the reaction flask, stir to dissolve it, and add 2,2-(1,6,7,8-tetrahydro -2H-indeno[5,4-B]furan-8-yl)ethanamine (100g, 0.487mol, 1eq) in methanol (0.5L) solution, kept dripping within 30 minutes, and stirred under reflux for two Hours, naturally cooled to room temperature and then stirred at 0-5 degrees Celsius for 5 hours, filtered, the filter cake was placed in a mixed solvent of ethyl acetate and methanol (1L, v:v=6:4), heated to 80 degrees Celsius to dissolve it all After natural cooling and crystallization, stir at 0-5 degrees Celsius for 5 hours, filter, add 1M aqueous sodium hydroxide solution to the filter cake to adjust the pH=10-12, stir for 15 minutes, filter, wash the filtrate to nearly neutral, 50 degrees Celsius After drying, 30 g of white solid was obtained, yield: 60%, ee: 95%.

Embodiment 3

[0024] Put S-ibuprofen (100g, 0.487mol, 1eq) and tetrahydrofuran (1L) into the reaction flask, stir to dissolve it, and add 2,2-(1,6,7,8-tetrahydro-2H -Indeno[5,4-B]furan-8-yl)ethylamine (100g, 0.487mol, 1eq) in methanol (0.5L) solution, kept dropping within 30 minutes, after dropping, refluxed and stirred for two hours, Naturally cooled to room temperature, stirred at 0-5 degrees Celsius for 5 hours, filtered, and the filter cake was placed in a mixed solvent of tetrahydrofuran and methanol (1L, v:v=6:4), heated at 80 degrees Celsius to dissolve it completely, and cooled naturally. After crystallization, stir at 0-5 degrees Celsius for 5 hours, filter, add 1M aqueous sodium hydroxide solution to the filter cake to adjust the pH=10-12, stir for 15 minutes, filter, wash the filtrate to nearly neutral, and dry at 50 degrees Celsius to obtain White solid 28g, yield: 56%, ee: 93%.

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Abstract

The invention provides a resolution method of a ramelteon intermediate, which comprises the following steps: (1) carrying out salification reaction on a compound (I) 2,2-(1,6,7,8-tetrahydro-2H-indeno[5,4-B]furyl-8-yl)ethylamine and a resolution reagent L-pyroglutamic acid in a methanol-containing organic solvent at 20-100 DEG C to obtain a ramelteon intermediate compound (II) crude product; and (2) recrystallizing the ramelteon intermediate compound (II) crude product in an organic solvent, and dissociating under the action of alkali to obtain the target product ramelteon intermediate compound (II). The reaction route of the method is disclosed in the specification.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, more particularly to a method for resolving ramelteon intermediates. Background technique [0002] Ramelteon (ramelteon), the chemical name is (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl Base] Propionamide is a new type of melatonin receptor agonist developed by Takeda Pharmaceutical Company of Japan. In September 2005, it was approved by the FDA to be marketed in the United States. The product name is Rozerem, which can be used to treat insomnia that is difficult to fall asleep, and has a definite effect on chronic insomnia and short-term insomnia. This product can selectively stimulate melatonin type 1 receptor and type 2 receptor (MT1, MT2), increase slow wave sleep (SWS) and rapid eye movement sleep (REW), thereby reducing insomnia. Ramelteon has quick onset, long duration of action, and few adverse reactions when taken orally. It is the first non-addictive inso...

Claims

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Application Information

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IPC IPC(8): C07D307/77
CPCC07D307/77C07B57/00C07B2200/07
Inventor 李卓才李苏杨
Owner SUZHOU JONATHAN NEW MATERIALS TECH
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