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Preparation method for high-purity roflumilast

A roflumilast, high-purity technology, applied in the field of medicine, can solve the problems of low single-step yield, difficult industrialization, difficult to separate by-products and the like, and achieves the effect of a simple preparation method

Active Publication Date: 2016-01-20
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Because raw material compound 3, contains 2 phenolic hydroxyl groups in the 4-dihydroxybenzaldehyde (I) molecule, and aldehyde group has stronger electron-withdrawing effect, makes the acidity of 4-position phenolic hydroxyl group stronger than 3-position, in Have higher activity when carrying out O-alkylation reaction, so when raw material and bromomethylcyclopropane or chlorodifluoromethane carry out O-alkylation reaction synthesis compound II or IV, will inevitably generate impurity compound III or V, may even further generate impurity 3,4-dicyclopropylmethoxybenzaldehyde or 3,4-bis(difluoromethoxy)benzaldehyde, and the single-step yield is very low, directly affecting roflumilast The total yield, and because can produce a lot of by-products that are difficult to separate, also bring certain difficulty to industrialization

Method used

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  • Preparation method for high-purity roflumilast
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Experimental program
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Embodiment 1

[0033] Embodiment 1: the synthesis of 3-hydroxyl-4-difluoromethoxybenzaldehyde

[0034]Add 138.1g (1mol) of 3,4-dihydroxybenzaldehyde to 1L of 6mol / L sodium hydroxide solution, add phase transfer catalyst tetrabutylammonium sulfide 13.8g, methyl chlorodifluoroacetate 180.5g (1.25mol), stirred, the solution reacted at 60°C-65°C for 3 hours, after the reaction was completed, diluted with 1L of water and extracted twice with 500mL of ethyl acetate, collected the water layer, added concentrated salt to adjust the pH to 2, and used 1.5L Ethyl acetate was extracted three times, the ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized from petroleum ether-ethyl acetate (3:1) to obtain 148.5 g of off-white crystals, Yield 78.9%, melting point 94.1-95.2 ℃, purity 99.57%, impurity 3-difluoromethoxy-4-hydroxybenzaldehyde 0.21%, impurity 3,4-bisdifluoromethylbenzaldehyd...

Embodiment 2

[0035] Embodiment 2: the synthesis of 3-hydroxyl-4-difluoromethoxybenzaldehyde

[0036] Add 138.1g (1mol) of 3,4-dihydroxybenzaldehyde to 1L of 7mol / L sodium hydroxide solution, add 16.6g of phase transfer catalyst tetrabutylammonium sulfide, and 180.5g of methyl chlorodifluoroacetate (1.3mol), stirred, the solution was reacted at 60°C-65°C for 3 hours, after the reaction was completed, diluted with 1L of water and extracted twice with 500mL of ethyl acetate, collected the water layer, added concentrated salt to adjust the pH to 2, and used 1.5L Ethyl acetate was extracted three times, the ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized with petroleum ether-ethyl acetate (3:1) to obtain 149.4 g of off-white crystals, Yield 79.4%, purity 99.45%.

Embodiment 3

[0037] Embodiment 3: the synthesis of 3-hydroxyl-4-difluoromethoxybenzaldehyde

[0038] Add 138.1g (1mol) of 3,4-dihydroxybenzaldehyde to 1.2L of 5mol / L sodium hydroxide solution, add phase transfer catalyst tetrabutylammonium sulfide 15.0g, methyl chlorodifluoroacetate 173.5 g (1.2mol), stirred, the solution was reacted at 60°C-65°C for 3 hours, after the reaction was completed, diluted with 1L of water and extracted twice with 500mL of ethyl acetate, collected the water layer, added concentrated salt to adjust the pH to 2, and used 1.5 L ethyl acetate was extracted three times, the ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized with petroleum ether-ethyl acetate (3:1) to obtain 148.0 g of off-white crystals , yield 78.7%, purity 99.24%.

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to a preparation method for high-purity roflumilast and an intermediate 3-hydroxy-4-diflouromethylbenzaldehyde of the roflumilast. The preparation method comprises the steps that the 3-hydroxy-4-diflouromethylbenzaldehyde is firstly obtained by taking 3-hydroxy-4-dihydroxybenzaldehyde as raw materails at higher yield and purity and then synthesized into 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde, the 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde is oxidized to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and finally the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid reacts with 4-amino-3,5-dichloropyridine to obtain the roflumilast. Due to the fact that the 3-hydroxy-4-diflouromethylbenzaldehyde with the higher yield and purity is obtained, the total yield of the roflumilast is increased, and many by-products which are difficult to separate cannot be generated.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of high-purity roflumilast and its intermediate 3-hydroxyl-4-difluoromethoxybenzaldehyde. Background technique [0002] Roflumilast (roflumilast), the chemical name is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, a German Altana The phosphodiesterase 4 (PDE4) inhibitor developed by the company was approved by the European Union in July 2010 for the first time in Germany. It is clinically used for the treatment of chronic obstructive pulmonary disease (COPD). The trade name is Daxas, and it was approved by the US FDA in March 2011. This product can reduce the release of inflammatory mediators by inhibiting PDE4, thereby inhibiting the damage to lung tissue caused by respiratory diseases such as COPD and asthma. [0003] Since the 1990s, chemists have started to study the synthetic method of roflumilast, and there ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07C47/575C07C45/64
CPCC07C45/64C07C47/575C07D213/75
Inventor 陈雨杨涛涛巩腾文
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD