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Method for synthesizing roflumilast

A technology of roflumilast and a synthesis method, which is applied to the synthesis field of roflumilast, can solve the problems of large-scale production danger, inconvenient scale-up production, low yield and the like, and achieves production safety, high purity and high purity. High yield, effect of reducing hygroscopicity

Active Publication Date: 2013-04-03
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above-mentioned method is a classic synthesis route of roflumilast, wherein the alkali used is sodium hydride, and the yield of this method is low, only about 50%, and the reaction will release hydrogen gas, which is very easy to cause an explosion once the hydrogen gas is not fully removed. Potentially dangerous for mass production
Due to the above problems of sodium hydride, researchers improved the synthesis method, such as patent number: 200480001216.4 (CN100471840C), which changed the base catalyst to potassium tert-butoxide, which improved the purity of the product. However, potassium tert-butoxide is a strong base Potassium salt has strong hygroscopicity. After being exposed to the air, water absorption can be observed within ten seconds. After absorbing water, decomposition reaction occurs immediately, which makes it inconvenient to scale up production in areas with high humidity.

Method used

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  • Method for synthesizing roflumilast
  • Method for synthesizing roflumilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 The synthetic method of roflumilast of the present invention

[0032] (1) Add 10.0g (about 0.039mol) 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (compound Ⅱ), 16ml toluene, 1.0ml DMF (about 0.013mol) into the reaction flask, stir dissolve. Then add SOCl 2 3.6ml (about 0.05mol), heated to 80°C and stirred for 1h. Stop stirring and heating, and evaporate residual SOCl under reduced pressure after cooling slightly 2 and toluene; use 50ml of dry DMF to dissolve and set aside.

[0033] (2) Add 9.5g (about 0.058mol) of 4-amino-3,5-dichloropyridine (compound IV) and 50ml of dry DMF into the reaction flask, stir to dissolve. Add 3.0g (about 0.077mol) NaNH in batches under ice-water bath 2 After the addition, rinse the wall of the reaction flask with 10ml DMF, and stir for 40min. The DMF solution of compound III prepared in the first step was added dropwise into the reaction flask, and the reaction was stirred at room temperature for 5 h after the addit...

Embodiment 2

[0038] Embodiment 2 The synthetic method of roflumilast of the present invention

[0039] (1) Add 50.0g (about 0.19mol) 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (compound Ⅱ), 75ml toluene, 2.0ml DMF (about 0.026mol) into the reaction flask, stir dissolve. Then add SOCl 2 18ml (about 0.248mol), heated to 70°C and stirred for 1h. Stop stirring and heating, and evaporate residual SOCl under reduced pressure after cooling slightly 2 and toluene; use 250ml of dry THF to dissolve and set aside.

[0040] (2) Add 47.4g (about 0.29mol) of 4-amino-3,5-dichloropyridine (compound IV) and 250ml of dry THF into the reaction flask, stir to dissolve. Add 19g NaNH in batches 2 (about 0.49mol), after adding, rinse the wall of the reaction flask with 50mlTHF. The reaction was stirred at room temperature for 40 min. The THF solution of compound III prepared in the first step was added dropwise into the reaction flask, and the reaction was stirred at room temperature for 5 h after t...

Embodiment 3

[0042] Embodiment 3 The synthetic method of roflumilast of the present invention

[0043] (1) Add 50.0g (about 0.19mol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (compound II), 75ml of toluene, and 0.114mol of DMF into the reaction flask, stir to dissolve. Then add 0.38molSOCl 2 , heated to 70 ° C and stirred for 1 h. Stop stirring and heating, and evaporate residual SOCl under reduced pressure after cooling slightly 2 and toluene; use 500ml of dry THF to dissolve and set aside.

[0044] (2) Add 52g (about 0.32mol) of 4-amino-3,5-dichloropyridine (compound IV) and 470ml of dry THF into the reaction flask, stir to dissolve. Add 25g NaNH in batches 2 (about 0.64mol), after adding, rinse the wall of the reaction flask with 50mlTHF. The reaction was stirred at room temperature for 40 min. The THF solution of compound III prepared in the first step was added dropwise into the reaction flask, and the reaction was stirred at room temperature for 5 h after the additi...

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Abstract

The invention provides a method for synthesizing roflumilast, which comprises the following steps: (1) taking 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid for reaction to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride or 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide; (2) after the reaction in step (1) is finished, performing amidation on the resultant and 4-amino-3,5-dichloropyridine by using sodium amide as a catalyst; and (3) after the reaction is over, purifying the resultant to obtain refined roflumilast, wherein the mole ratio of sodium amide to 4-amino-3,5-dichloropyridine is greater than or equal to 1. The method uses the specific inorganic base catalyst, namely sodium amide, based on the current roflumilast synthesis process to guarantee the high purity and yield of the product and the production safety and reduce the hygroscopicity of the raw materials. Therefore, the method is more favorable for the industrial mass production.

Description

technical field [0001] The present invention relates to the synthetic method of roflumilast. Background technique [0002] Roflumilast, chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide , its CAS number is: 162401-32-3, and its structural formula is as follows: [0003] [0004] Roflumilast is used to treat chronic obstructive pulmonary disease (COPD), reduce the frequency of acute exacerbation (exacerbation) of severe COPD, relieve the exacerbation of lung and airway inflammation; it is a phosphodiesterase 4 (PDE4) inhibitor, mainly expressed Inflammatory cells associated with asthma, including eosinophils, neutrophils, and mast cells; the drug can specifically act on proteases involved in smooth muscle contraction, prevent cAMP degradation, thereby blocking pro-inflammatory response signaling, thus It has anti-inflammatory activity and has achieved good curative effect in the clinical treatment of asthma and chronic obstru...

Claims

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Application Information

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IPC IPC(8): C07D213/75
Inventor 王朝阳马静君郭培良黄耀宗王利春沈芃梁隆程志鹏
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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