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Preparation method of roflumilast N-oxide

A technology of roflumilast and compounds, which is applied in the field of preparation of roflumilast N-oxide, can solve the problems of high price, long reaction time, low yield, etc., and achieve convenient post-processing, high product purity, and reaction The effect of high yield

Inactive Publication Date: 2016-12-28
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The oxidant MMPP of this route is expensive, the reaction time is long, and the silica gel column chromatography is purified, the yield is not high, and the peroxide is easy to remain, so it is not suitable for industrial production.
[0014] 3) Xiang Zuojuan, Sun Hongbin, Synthesis and crystal form research of roflumilast N-oxide, Journal of China Pharmaceutical University (2012), 43(6), 492-496 discloses that roflumilast and m-chloroperoxide Oxybenzoic acid reaction, separated by silica gel column chromatography, but its peroxide is easy to remain

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0049] Preparation of Roflumilast N-oxide

[0050]

[0051]Add roflumilast (5 g, 12.4 mmol), acetic acid (24 mL), and 30% hydrogen peroxide (6.3 mL, 62 mmol) into a three-necked reaction flask, heat up to 70° C. and stir for 6 hours. After the reaction was completed, cool to room temperature, pour the reaction solution into 150 mL ice water, add sodium carbonate to adjust the pH value to 7-8, and extract the aqueous phase with ethyl acetate (150 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain roflumilast N-oxide (HPLC purity 96.9%).

[0052] Recrystallization:

[0053] The obtained product roflumilast N-oxide was added into isopropanol (50 mL), heated to 80° C. under stirring, and dissolved completely in about 20 minutes, and continued to stir for 30 minutes. The solution was naturally cooled to room temperature, a white solid was precipitated, filtered with suction, and the filter cake was washed with col...

Embodiment 2

[0057] Preparation of Roflumilast N-oxide

[0058] Roflumilast (5g, 12.4mmol), acetic acid (24mL), and 30% hydrogen peroxide (6.3mL, 62mmol) were added into the reaction flask, heated to 30°C and stirred for 133 hours. After the reaction is completed, cool the reaction liquid, pour it into 150 mL of ice water, add sodium carbonate to adjust the pH to 7-8, extract the aqueous phase with ethyl acetate (150 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and filter , concentrated to obtain roflumilast N-oxide (HPLC purity 92.9%).

[0059] Referring to the recrystallization method in Example 1, the purified white solid roflumilast N-oxide (4.0 g, yield 76.9%, HPLC purity 95.1%) was obtained through recrystallization.

Embodiment 3

[0061] Preparation of Roflumilast N-oxide

[0062] Add roflumilast (5 g, 12.4 mmol), acetic acid (24 mL), and 30% hydrogen peroxide (6.3 mL, 62 mmol) into the reaction flask, heat up to 40° C. and stir for 83 hours. After the reaction is completed, cool the reaction solution to room temperature, pour it into 150 mL of ice water, add sodium carbonate to adjust the pH to 7-8, extract the aqueous phase with ethyl acetate (150 mL×3), combine the organic phases, and dry over anhydrous sodium sulfate , filtered and concentrated to obtain roflumilast N-oxide (HPLC purity 95.1%).

[0063] Referring to the recrystallization method in Example 1, the purified white solid roflumilast N-oxide (4.2 g, yield 80.8%, HPLC purity 96.4%) was obtained through recrystallization.

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Abstract

The invention relates to a preparation method of a roflumilast N-oxide, which is the preparation method of a compound shown in a formula (I). The preparation method has the advantages of high reaction yield, high product purity and convenient post-treatment, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of roflumilast N-oxide. Background technique [0002] Roflumilast was developed by Altana Pharma, the first selective phosphodiesterase 4 (PDE-4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD), most of which are metabolized into Roflumilast in the human body N-oxide N-(3,5-dichloro-1-oxo-pyridin-4-yl)-3-cyclopropanemethoxy-4-difluoromethoxycarboxamide, roflumilast The activity of N-oxide is only 2 to 3 times weaker than that of roflumilast, and it also has higher PDE-4 selectivity. About 90% of the PDE-4 inhibition in the human body is caused by roflumilast N-oxide produced, the other 10% was produced as roflumilast prototype. [0003] The chemical structure of roflumilast is as formula (II): [0004] [0005] The chemical structure of roflumilast N-oxide is as formula (I): [0006] [0007] Compared with roflumilast, roflumilast N-oxide can directly inhibit cell proli...

Claims

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Application Information

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IPC IPC(8): C07D213/89
CPCC07D213/89
Inventor 李瑶肖至阳
Owner SICHUAN HAISCO PHARMA CO LTD
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