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Refining method for high-purity roflumilast

A technology of roflumilast and a refining method, which is applied in the refining field of high-purity roflumilast, can solve the problem of low yield and the like, and achieve the effects of good appearance, high yield and high purity

Inactive Publication Date: 2014-01-08
国药集团致君(苏州)制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing methods generally need to be refined many times to obtain qualified products, resulting in low yields.

Method used

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  • Refining method for high-purity roflumilast
  • Refining method for high-purity roflumilast
  • Refining method for high-purity roflumilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation of embodiment 1 roflumilast crude product

[0025] The preparation of roflumilast crude product adopts the document WO09501338 method: 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid A is reacted with thionyl chloride to obtain acid chloride B, and then sodium hydrogen Roflumilast is prepared by condensation of base and 3,5-dichloro-4-aminopyridine, and the crude product of roflumilast is obtained, with a general HPLC purity of 98-99%.

[0026] The reaction formula is as follows:

[0027]

[0028] Specifically, the following steps are included:

[0029] 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (A) (282.5g, 1.094mol) was dissolved in toluene (2.8L), and SOCl was added 2 (260.3g, 2.188mol), the external temperature was raised to 110°C for reflux reaction, and a tail gas (HCl) receiving device was added. The reaction was complete after 1 h. Evaporate the solvent and volatile matter (below 90°C) under reduced pressure, add 560ml o...

Embodiment 2

[0033] Add 50g of crude roflumilast and 200ml of ethyl acetate into a 500ml flask, stir, heat to dissolve, cool slightly, add 1.5g of activated carbon, stir and decolorize under reflux for 30min, filter, stir and crystallize the filtrate at room temperature for 10 hours, filter, acetic acid Wash with 20ml of ethyl ester, and dry at 60°C to obtain 35.8g of white crystals, with a yield of 71.6%, a purity of 99.84%, and a single impurity of less than 0.1%.

[0034] The roflumilast sample prepared in embodiment 2 was carried out 1 HNMR (δppm) analysis, see figure 1 , 2 , 10.57(s, 1H, heavy water exchange disappeared), 8.73(s, 2H), 7.72(d, 1H, J=1.6Hz), 7.65(dd, 1H, J=1.6, 8.4Hz), 7.35(d, 1H ,J=8.4Hz),7.19(t,1H,J=74Hz),4.00(d,2H,J=7.2),1.29-1.25(m,1H),0.61-0.56(m,2H),0.39-0.35 (m,2H).

[0035] The roflumilast sample prepared in embodiment 2 is carried out mass spectrometry analysis, see image 3 . ESI + , 402.98 (M+H + ,100%), chlorine isotope peak 404.98 (64%); ESI-, 400.9...

Embodiment 3

[0045] Add 50g of roflumilast crude product and 300ml of acetone into a 500ml flask, stir, heat to dissolve, cool slightly, add 2.5g of activated carbon, stir for decolorization for 30min, filter, stir and crystallize the filtrate at room temperature for 8 hours, filter, wash with 20ml of acetone, 60°C After drying, 37.0 g of white crystals were obtained, with a yield of 74.0%, a purity of 99.86%, and a single impurity of less than 0.1%.

[0046] The roflumilast sample prepared in Example 3 was detected by DSC and X-powder diffraction, and the results were the same as in Comparative Example 1.

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Abstract

The invention provides a refining method for high-purity roflumilast. The refining method includes: dissolving a crude product of the roflumilast into a solvent, adding activated carbon for decolorization processing, filtering, and subjecting filtered liquor to standing for crystallization prior to washing and drying to obtain roflumilast powder with the purity more than 99.5%. The solvent is selected from one or several of ethyl acetate, acetone, butanone, normal butanol, dioxane and isopropyl ether. The refining method is simple in process; the high-purity roflumilast can be obtained through primary crystallization, and the obtained roflumilast is good in appearance, high in yield, high in purity (single impurity is lower than 0.1%, and total impurity is lower than 0.5%), single in crystal form and applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for refining high-purity roflumilast. Background technique [0002] Roflumilast, CAS: 162401-32-3, chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(di Fluoromethoxy) benzamide, the structural formula is as follows: [0003] [0004] It is a drug jointly developed by Nycomed of Switzerland and Forest of the United States. In July 2010, it was approved in the European Union as an auxiliary bronchodilator in the maintenance treatment of patients with severe chronic obstructive pulmonary disease. The trade name is Daxas. The first new oral drug approved globally for the treatment of COPD. It was launched in the United States on February 28, 2011, under the product name DALIRESP. Roflumilast is a once-a-day oral tablet that selectively inhibits PDE4, blocks inflammatory response signal transmission, and then inhibits damage to lung tissue caused b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 黄火明陈亮刘珍仁郝群汤庆佳
Owner 国药集团致君(苏州)制药有限公司
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