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Preparation method for key intermediate of ramelteon

A technology of ramelteon and intermediates, applied in the field of compound preparation, can solve the problems of inaccessibility, etc., and achieve the effect of novel synthetic route, high yield and short synthetic linearity

Active Publication Date: 2014-06-25
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the current literature, it is still impossible to obtain the compound of structural formula (I) conveniently

Method used

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  • Preparation method for key intermediate of ramelteon
  • Preparation method for key intermediate of ramelteon
  • Preparation method for key intermediate of ramelteon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1. Synthesis of ethyl 2-(6,7-dihydro-1H-indeno[5,4-b]furan-8(2H)-ylidene)acetate (I)

[0032] The chemical reaction formula of embodiment 1 is as follows:

[0033]

[0034] In a dry sealed tube, add formula 1 compound (76g, 367mmol), formula 2 compound (24g, 73.4mmol), triphenylphosphine (3.85g, 14.7mmol), cesium carbonate (143.5g, 440mmol), norbornene ( 34.6g, 367mmol), palladium acetate (1.65g, 7.34mmol), add 240mL dry DME to dissolve, seal the tube at 100°C for 48 hours, complete the reaction, filter, concentrate, dissolve EA (ethyl acetate), wash twice with water , saturated saline, dried over anhydrous sodium sulfate, concentrated, first PE column chromatography, not isolated pure, petroleum ether: ethyl acetate (PE:EA, volume ratio) = 30:1 column chromatography, a pair of cis-trans Isomers: 3.55 g (pale yellow solid) and 11 g (yellow oil), yields of 20% and 61%, respectively.

[0035] Formula (I) compound isomer one: 1 H NMR (400MHz, CDCl 3 )δ7.09(d...

Embodiment 2

[0037] Example 2. Synthesis of ethyl 2-(6,7-dihydro-1H-indeno[5,4-b]furan-8(2H)-ylidene)acetate (I)

[0038] The chemical reaction formula of embodiment 2 is as follows:

[0039]

[0040]In a dry sealed tube, add the compound of formula 1 (1.52g, 7.34mmol), the compound of formula 2 (2.4g, 7.34mmol), triphenylphosphine (385mg, 1.47mmol), cesium carbonate (14.35g, 44mmol), norbornanol After ethylene (3.46g, 36.7mmol) and palladium acetate (165mg, 0.74mmol), add 15mL of dry DME to dissolve, seal the tube at 100°C for 48 hours, complete the reaction, filter, concentrate, wash 2 times with water after EA dissolves, and wash with saturated salt Water, dried over anhydrous sodium sulfate, concentrated, first PE column chromatography, not isolated pure, PE:EA=30:1 column chromatography, obtained a pair of cis-trans isomers: 181mg (light yellow solid) and 540mg (yellow solid) oil), the yields were 10% and 31%, respectively.

Embodiment 3

[0041] Example 3. Synthesis of ethyl 2-(6,7-dihydro-1H-indeno[5,4-b]furan-8(2H)-ylidene)acetate (I)

[0042] The chemical reaction formula of embodiment 3 is as follows:

[0043]

[0044] In a dry sealed tube, add the compound of formula 1 (4.56g, 22mmol), the compound of formula 2 (2.4g, 7.34mmol), triphenylphosphine (385mg, 1.47mmol), cesium carbonate (14.35g, 44mmol), norbornene (3.46g, 36.7mmol), palladium acetate (165mg, 0.74mmol), add 240mL of dry DME to dissolve, seal the tube at 100°C for 48 hours, complete the reaction, filter, concentrate, wash 2 times with water after EA dissolves, and wash with saturated saline , dried over anhydrous sodium sulfate, concentrated, first PE column chromatography, not isolated pure, PE:EA=30:1 column chromatography, to obtain a pair of cis-trans isomers: 287mg (light yellow solid) and 880mg (yellow oily material), the yields were 16% and 49%, respectively.

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Abstract

The invention discloses a preparation method for a key intermediate of ramelteon (a compound represented by formula (I)). The preparation method includes the steps as follows: dissolving a compound represented by formula 1, a compound represented by formula 2, a metal catalyst, an alkali, norbornene and a ligand in an organic solvent for carrying out a reaction to obtain the compound represented by formula (I). The synthetic route of the invention is a convergent synthesis which is different from a linear synthesis in a conventional synthetic route. The synthetic route of the invention is short in linearity and is high in yield. The reaction equation of the invention is represented by a formula as follows.

Description

technical field [0001] The present invention relates to a preparation method of a compound, in particular to a key intermediate of ramelteon 2-(6,7-dihydro-1H-indeno[5,4-b]furan-8(2H)-ylidene A new preparation method of ethyl acetate (compound of formula I). [0002] Background technique [0003] Ramelteon (Ramelteon), the chemical name is (S)-N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)] Propionamide, developed by Japan's Takeda Company, was approved by the US FDA in September 2005. Raltiamide is a melatonin receptor agonist that can mimic the physiological effects of melatonin secreted by the pineal gland, helping to regulate the sleep cycle and improve sleep quality. Its mechanism of action is: this product is a melatonin receptor agonist, and melatonin MT 1 and MT 2 Receptors have higher affinity for MT 1 and MT 2 Receptors exhibit specific full agonism, not associated with MT 3 Receptor role. In addition, it does not bind to neurotransmitter receptors...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
CPCC07D307/77
Inventor 陈友喜郜飞付小旦陈义朗
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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