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Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine

A technology of difluoromethoxybenzamide and cyclopropylmethoxy, which is applied in the field of medicinal chemistry preparation, can solve the problems of low yield, optimization of synthesis method, difficult impurity control and the like, and achieves simple and convenient post-processing. The effect of high production operation, purity and yield

Active Publication Date: 2012-02-01
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] International patents WO2005 / 026095, WO2006 / 040645, and WO2008 / 006509 have introduced a series of preparation methods for PDE4 inhibitors including roflumilast, but still all use 3-cyclopropylmethoxy-4-bis The active derivative of fluoromethoxybenzoic acid directly reacts with the compound of formula V, the synthesis method of roflumilast is not optimized, and there are also problems of difficult impurity control and low yield

Method used

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  • Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine
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  • Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: Preparation of 3-cyclopropylmethoxy-4-dichloromethoxybenzoic acid p-nitrophenol

[0035]

[0036] Under nitrogen protection and stirring in an ice bath, 3.31g of p-nitrophenol was added to 60ml of dichloromethane, and partly dissolved to form a suspension. After adding 6.6ml of triethylamine, p-nitrophenol was completely dissolved, and 5.66g of 3- A solution of cyclopropylmethoxy-4-difluoromethoxybenzoic acid freshly prepared acid chloride in 30 ml of dichloromethane was added dropwise to the above solution, and the temperature was raised to 20° C. and stirred after the dropwise addition. TLC showed that after the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 50ml of absolute ethanol was added to the residue to stir, filtered, washed with 50ml of water, and washed with a small amount of absolute ethanol to obtain a white solid, which was dried to obtain 7.65g of the product, with a content > 98%, two steps...

Embodiment 2

[0037] Embodiment 2: the preparation of roflumilast

[0038]

[0039] Under nitrogen protection and stirring in an ice bath, 3.24g of 4-amino-3,5-dichloropyridine was dissolved in 30ml of N,N-dimethylformamide, and 1.44g of sodium hydride (60%) was added in batches, and kept stirring After 15 minutes, a solution of 6.84g of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid p-nitrophenyl in 45ml of N,N-dimethylformamide was added dropwise to the above mixture After the dropwise addition, the temperature was raised to 10°C and stirred. About 15 minutes later, TLC showed that the reaction was complete. Slowly add 10ml of water dropwise under ice bath, pour the reaction liquid into 350ml of water, adjust the pH to 3.2, a large amount of white solid precipitated, filtered, washed with a small amount of water and dried in vacuum to obtain the crude product of roflumilast 6.89 g.

[0040] Add 45ml of 90% (V / V) ethanol to the above-mentioned roflumilast crude product, heat and r...

example 3

[0042] Example 3: Preparation of Roflumilast

[0043]

[0044] Under nitrogen protection and stirring at 20°C, 1.75g ​​of 4-amino-3,5-dichloropyridine was dissolved in 15ml of N,N-dimethylformamide, 0.87g of sodium hydroxide was added, and the 2.74 The solution of g 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid p-nitrophenyl ester in 20ml N,N-dimethylformamide was added dropwise to the above mixture, and the stirring was continued at 50°C After 5 hours, TLC showed that the reaction was complete. The reaction solution was poured into 180ml of water, and the pH was adjusted to 2. A large amount of white solid precipitated, filtered, washed with a small amount of water, and dried in vacuum to obtain 2.12g of crude roflumilast.

[0045] Add 15ml of 80% (V / V) ethanol to the above-mentioned roflumilast crude product, heat and reflux for 50 minutes, stir, and after clarification, cool and crystallize naturally for 8 hours, separate out the solid filter, and obtain refined rof...

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Abstract

The invention discloses a method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine, which is implemented by carrying out amidation reaction on anions of 4-amino- -3,5-dichloropyridine and 3-cyclopropylmethoxy-4-difluoro-aryl-methoxybenzoate under inert solvent neutralized alkaline conditions. The preparation method disclosed by the invention has the advantages of mild reaction conditions, fewer byproducts and simple after-treatment, and obviously lowers the synthesis cost; the purity of the refined product is at least 99.8%; and the invention is more suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical preparation, and specifically relates to a structural formula of N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, which is commonly used The preparation method named Roflumilast. Background technique [0002] Roflumilast, as the first selective phosphodiesterase 4 (PDE 4) inhibitor, was approved by the European Union on July 6, 2010 for the treatment of chronic obstructive pulmonary disease (COPD). Roflumilast can improve lung function and reduce the rate of acute exacerbation of chronic bronchitis. The currently reported preparation methods are as follows: [0003] International patents WO93 / 25517 and WO94 / 02465 describe the preparation of dialkoxy-substituted benzamides by reacting reactive derivatives of benzoic acid with amines. Wherein the active derivative of benzoic acid is acid halide or acid anhydride. The reaction can be carried out in an organic ba...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
Inventor 王颖闫革新李泽林
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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