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Method for preparing high-purity roflumilast

A compound, selected technology, applied in the preparation of carbon-based compounds, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of expensive, complicated operation, high cost, etc.

Inactive Publication Date: 2012-07-25
CENTAURUS BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] Low temperature reaction is used in this route, and bromine is used, and expensive palladium catalyzed reaction is used, the operation is complicated, the cost is high, and it is not suitable for industrial production

Method used

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  • Method for preparing high-purity roflumilast
  • Method for preparing high-purity roflumilast
  • Method for preparing high-purity roflumilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: Preparation of 3-(cyclopropylmethoxy)-4-methoxybenzaldehyde (compound 3)

[0055] Add 3-hydroxy-4-methoxybenzaldehyde (compound 1, 15.2g, 0.1mol), bromomethylcyclopropane (compound 2, wherein X is Br, 16.2g, 0.12mol), potassium carbonate to the reaction flask (41.4 g, 0.36 mol) and DMF (200 mL). The mixture was reacted at room temperature for 8 hours, and the reaction was complete by TLC. Ethyl acetate (200 mL) was added to the reaction solution, followed by washing with distilled water. The aqueous and organic phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound 3 as 20.2 g of off-white solid with a yield of 98%.

[0056] 1 H NMR (CDCl 3 ): δ9.84(1H, s), 7.47-7.44(1H, d, J=2.0Hz), 7.39(1H, s), 6.98-7.00(1H, d, J=8.4Hz), 3.97(3H, s), 3.97-3.92 (2H, d, J=22Hz), 1.30-1.32 (1H, m), 0...

Embodiment 2

[0057] Embodiment 2: Preparation of 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde (compound 4)

[0058] Compound 3 (10.3 g, 50 mmol) was dissolved in NMP (150 mL), and an aqueous solution of sodium thiophenate (~36.7% w / w, 0.1 mol) was added. The obtained mixed solution was stirred and reacted at 190-200° C. for 1 hour, and then cooled to room temperature. The reaction mixture was poured into distilled water (500 mL), extracted with ethyl acetate (2 x 100 mL). The aqueous phase was adjusted to pH 1-2 with hydrochloric acid (6.0M), and extracted with ethyl acetate (3×100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound 4 as 7.68 g of off-white solid with a yield of 80%.

[0059] 1 H NMR (CDCl 3 ): δ9.81(1H, s), 7.43-7.40(1H, d, J=2.0Hz), 7.38(1H, s), 7.06-7.04(1H, d, J=4.0Hz), 3.96-3.94( 2H, d, J = 6.8 Hz), 1.33-1.29 (1H, m), 0.70-0.66 (2H, m), 0.39-0.36 (2H, m).

Embodiment 3

[0060] Embodiment 3: Preparation of 3-(cyclopropylmethoxy)-4-difluoromethoxybenzaldehyde (compound 5)

[0061] Compound 4 (5.77g, 30mmol), K 2 CO 3 (12.42g, 90mmol) and DMF (100mL) were mixed in a three-necked flask, and then Freon gas was introduced to react at 45°C for 6 hours. TLC showed the reaction was complete. The reaction solution was poured into distilled water, and extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound 5 as 7.05 g of yellow oily liquid with a yield of 97%.

[0062] 1 H NMR (CDCl 3 ): δ9.92(1H, s), 7.47-7.44(1H, d, J=2.0Hz), 7.43(1H, s), 7.32-7.30(1H, d, J=4.0Hz), 6.94-6.57( 1H, d, J = 150Hz), 3.96-3.94 (2H, d, J = 6.8Hz), 1.34-1.30 (1H, m), 0.70-0.65 (2H, m), 0.39-0.36 (2H, m).

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Abstract

The invention discloses a method for preparing high-purity roflumilast which is a compound as shown in the formula (I). The compound is an orally taken selective phosphodiesterase 4 (PDE4) inhibitor and is proven to be capable of inhibiting inflammation related to a chronic obstructive pulmonary disease (COPD).

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing high-purity roflumilast. Background technique [0002] Roflumilast, chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide , the structural formula is as follows: [0003] [0004] Roflumilast is a new oral drug developed by Nycomed for the treatment of asthma and chronic obstructive pulmonary disease. Roflumilast was approved by the EU in June 2010 as being used for severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis, and its trade name is Daxas in EU countries. On February 28, 2011, the US FDA approved it for the treatment of severe COPD, and its trade name in the US is Daliresp. [0005] Roflumilast is an oral, selective phosphodiesterase 4 (PDE4) inhibitor. The drug has been shown to suppress inflammation associated with chronic obstructive pulmonary disease (COPD). Roflumilast is n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07C47/575C07C45/64
Inventor 杨利民王宏张晓军校登明韩永信
Owner CENTAURUS BIOPHARMA
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