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Preparation method for roflumilast intermediate

A technology of roflumilast and intermediates, which is applied in the preparation of organic compounds, the preparation of carboxylate, chemical instruments and methods, etc., can solve the problems of severe reaction, large consumption of raw materials, poor reaction selectivity, etc., and achieve mild reaction conditions. , post-processing simple effects

Inactive Publication Date: 2012-06-20
NANJING TIANHAI MEDICAL TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0009] (1) 3,4-dihydroxybenzaldehyde to 3-hydroxyl-4-difluoromethoxybenzaldehyde, the reaction selectivity is poor, and the resulting product aftertreatment needs to be separated by column chromatography, and the yield is too low (25%~30 %), not suitable for industrialized production;
[0010] (2) 3-hydroxyl-4-difluoromethoxybenzaldehyde to 3-cyclopropylmethoxyl-4-difluoromethoxybenzaldehyde, using tetrahydrofuran as a solvent, the reaction time is long (14h), and it takes 3 times the equivalent of bromomethylcyclopropane as the substrate, the consumption of raw materials is too large;
[0011] (3) In the preparation process of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde to 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, sodium chlorite The aqueous solution is added to the solution prepared by 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde, sulfamic acid and glacial acetic acid, the reaction is very violent, the reaction conditions are not easy to control, and the cost is high

Method used

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  • Preparation method for roflumilast intermediate
  • Preparation method for roflumilast intermediate
  • Preparation method for roflumilast intermediate

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Experimental program
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Embodiment 4

[0030] The preparation of embodiment 4-benzyloxy-3-hydroxybenzaldehyde (IV):

[0031] Add acetone (600ml), 3,4-dihydroxybenzaldehyde (II) (60.0g, 434mmol) in the reaction flask, benzyl bromide (74.0g, 434mmol), anhydrous potassium carbonate (90.0g, 651mmol), stir, Heat to reflux for 3h, filter, concentrate the filtrate under reduced pressure, add ethyl acetate (600ml), extract with 1N NaOH aqueous solution (600ml×2), combine the aqueous layers, neutralize with 1N hydrochloric acid (1200ml), add ethyl acetate (600ml), organic The layer was washed with saturated disodium hydrogen phosphate aqueous solution (300ml×2), dried over anhydrous sodium sulfate, filtered, concentrated and solidified, and recrystallized from ethanol to obtain 67.5g of light yellow crystals, yield 68%, mp 120~122°C. 1 H NMR (300MHz, CDCl 3 )δ: 5.84(s, 1H, OH), 7.03(d, J=8.0Hz, 1H, Ar-H), 7.37~7.45(m, 7H, Ar-H), 5.20(s, 2H, CH 2 ), 9.82 (s, 1H, CHO).

[0032] The preparation of embodiment 4-benzyloxy-3-c...

Embodiment 3

[0036] The preparation of embodiment 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (VII):

[0037] Add DMF (450ml), 4-hydroxyl-3-cyclopropylmethoxybenzaldehyde (V) (45g, 232mmol), potassium carbonate (64.1g, 464mmol) into the reaction flask, after heating up to 60°C, feed difluoro Chloromethane gas for 8 hours, filtered, concentrated under reduced pressure, 2N sodium hydroxide solution (500ml) was added to the residue, extracted with dichloromethane (400ml×2), the organic layers were combined, dried over anhydrous sodium sulfate and filtered, the filtrate Concentrate under reduced pressure to obtain 53.8 g of light yellow transparent liquid with a yield of 96%.

Embodiment 3

[0038] The preparation of embodiment 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (I):

[0039] At 65°C, 30% hydrogen peroxide (103ml, 1030mmol) was added into a mixture of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (VI) (50g, 207mmol), 50% potassium hydroxide (60.6ml, 827mmol ) and methanol (500ml), stirred for 1h. After the reaction, water (1.5 L) was added, and concentrated hydrochloric acid was added to adjust the pH to 2. After suction filtration and drying of the filter cake, 51.5 g of off-white solid was obtained, yield 96%, mp 118-120°C. ESI-MS (m / z): 257[M-H]-; 1 H NMR (300MHz, CDCl 3 )δ: 0.34 ~ 0.36 (m, 2H, CH 2 C H 2 CH), 0.62~0.68(m, 2H, CH 2 C H 2 CH), 1.28(m, 1H, CH), 3.90(d, J=6.7Hz, 2H, CHC H 2 O), 6.71(t, 1H, J=75.0Hz, CHF 2 ), 7.18 (d, J=7.2Hz, 1H, Ar-H), 7.62-7.64 (m, 2H, Ar-H).

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Abstract

The invention discloses a preparation method for a roflumilast intermediate. The preparation method is characterized by comprising the following steps of: etherifying 3,4-dihydroxy benzaldehyde serving as a raw material and 3-hydroxyl by using benzene ring non-substituted, mono-substituted or poly-substituted benzyl protection 4-hydroxy and halogenated methyl cyclopropane; performing catalytic hydrogenolysis to obtain 4-hydroxy-3-cyclopropyl methoxy-benzaldehyde; etherifying and oxidizing the 4-hydroxy-3-cyclopropyl methoxy-benzaldehyde with difluoromonoch-loromethane to obtain 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid (I) serving as the roflumilast intermediate. The preparation method has the advantages of easiness and convenience for operating, mild reaction conditions, stable quality, simple post-treatment and no need of complex operation such as column chromatography and the like, and is suitable for industrial production.

Description

technical field [0001] A kind of preparation method of roflumilast intermediate technical background [0002] Roflumilast (roflumilast), the chemical name is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, a German Altana The phosphodiesterase 4 (PDE4) inhibitor developed by the company was approved by the European Union for the first time in Germany in July 2010. It is clinically used for the treatment of chronic obstructive pulmonary disease (COPD). The trade name is Daxas. It was also approved by the US FDA in March 2011. listed. This product can reduce the release of inflammatory mediators by inhibiting PDE4, thereby inhibiting the damage to lung tissue caused by respiratory diseases such as COPD and asthma. The structural formula of Roflumilast is as follows: [0003] [0004] Roflumilast [0005] 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (I) is the key intermediate of roflumilast, according to the literature WO2008142542, W...

Claims

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Application Information

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IPC IPC(8): C07C65/26C07C51/285
Inventor 陈国华钟永刚李昂江传亮
Owner NANJING TIANHAI MEDICAL TECH
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