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Synthesis method of ramelteon

A technology of ramelteon and a synthesis method, which is applied in the field of synthesis technology of amine derivatives-ramelteon, can solve the problems of low yield and insignificant improvement of ee value, and achieves easy scale-up production, few steps, and safety. good effect

Inactive Publication Date: 2015-04-22
JIANGSU SINOBIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] When choosing a chiral resolving agent, it was found that when resolving with L-DBTA, the ee value obtained after two recrystallizations of the obtained resolution salt was at most 70%, and the ee value obtained after three recrystallizations was 95% %, the ee value does not increase significantly after further refining, and the yield is low

Method used

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  • Synthesis method of ramelteon
  • Synthesis method of ramelteon
  • Synthesis method of ramelteon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Synthesis of compound 2--(1,6,7,8--tetrahydro--2H--indeno [5,4--b] furan--8--yl) ethylamine

[0048] 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (30g, 0.125mol) was added to water (600ml), Stir and cool to 0-5°C, add 20% NaOH (75ml, 0.375mol) dropwise, and control the temperature not to exceed 10°C during the dropwise addition. The reaction was stirred for 1 h.

[0049] Add EA 200ml*3 to extract three times, and combine the organic phases. Washed with water, washed with saturated NaCl, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain 25 g of light yellow oil (yield 98%).

Embodiment 2

[0050] Example 2: (S)--2--(1,6,7,8--tetrahydro--2H--indeno[5,4--b]furan--8--yl)ethylamine- Synthesis of -(S)--(+)--2--(4--isobutylphenyl)propionate

[0051] Take S-ibuprofen (25.5g, 0.124mol), add methanol (127ml), and stir to dissolve. A solution of the above free ethylamine (25 g, 0.123 mol) in methanol (125 ml) was slowly added dropwise at 25-30°C. After the dropwise addition, stirring and crystallization were continued overnight at room temperature. 37.5 g of white solid was obtained by filtration.

[0052] Add 187.5ml of methanol to 37.5g of the above solid, reflux to dissolve, and cool down to crystallize naturally. Filtration yielded 16.7 g. Reflux the solution with 147ml of methanol and crystallize at room temperature naturally. Filtration yielded 10.7 g. Reflux the solution with 100ml of methanol, cool down and crystallize naturally. 7.9 g of white solid was obtained by filtration. (yield 31.3%, ee value: 99.7%: 0.3%)

Embodiment 3

[0053] Example 3: (S)--2--(1,6,7,8--tetrahydro--2H--indeno[5,4--b]furan--8--yl)ethylamine synthesis

[0054] Add water (80ml) to 7.9g of the above white solid, stir and cool to below 5°C, add dropwise 20% NaOH to adjust the pH to 11-12, and stir for 0.5h. Extract three times with DCM 25ml*3, and combine the organic phases.

[0055] The organic phase was washed with water and saturated NaCl, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 3.68 g of an off-white oil (93% yield).

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Abstract

The invention discloses a synthesis method of ramelteon, which can obtain high-purity ramelteon by five steps. The HPLC (high performance liquid chromatography) purity is higher than 99.8%, the optical purity is higher than 99.7%, the resolution yield and purity (29-35%) are much higher than those of the ramelteon resolved by other chiral resolving agents, and the total yield is 20-25%. The method has the following advantages of fewer steps and high safety, and can easily implement scale-up production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a synthesis process for preparing a high-purity optically active amine derivative-ramelteon with high yield. Background technique [0002] The main part of ramelteon is a propionylation part, and the modification part is an indenofuryl ethylamino part. According to bibliographical reports, the synthesis of ramelteon mainly contains following 5 kinds of methods, and its synthetic process difference is: [0003] The first synthetic method: use indenofuranone as a raw material to obtain indenofurylidene acetonitrile by Witting-Horner reaction, and obtain the key intermediate indenofurylidene acetic acid through catalytic hydrogenation and hydrolysis, and use amino-containing chiral reagents to obtain indenofurylidene acetonitrile The optical isomers were obtained by resolution, and then the target compound was obtained through ammoniation, reduction and prop...

Claims

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Application Information

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IPC IPC(8): C07D307/77
CPCC07D307/77
Inventor 黄乐群王磊胡丰锦
Owner JIANGSU SINOBIOPHARMA
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