Preparation method of 4-difluoromethoxy-3-hydroxybenzaldehyde

A technology of difluoromethoxybenzaldehyde and hydroxyl group, which is applied in the field of preparation of 3-hydroxy-4-difluoromethoxybenzaldehyde, can solve the problems of low product yield, cumbersome post-processing and high cost, and achieves a product high yield effect

Inactive Publication Date: 2013-12-25
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved by the present invention is in order to overcome in the existing 3-hydroxyl-4-difluoromethoxybenzaldehyde preparation method, the reaction conversion rate is low, the product yield is low, the cost is high, and aftertreatment is loaded down with trivial details and other defects, And a kind of preparation method of 3-hydroxyl-4-difluoromethoxybenzaldehyde is provided

Method used

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  • Preparation method of 4-difluoromethoxy-3-hydroxybenzaldehyde

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Embodiment 1

[0016] Embodiment 1: the preparation of 3,4-dihydroxybenzaldehyde

[0017]

[0018] Add vanillin (compound 1) (100.00g) and anhydrous dichloromethane (195ml) into a 1000ml four-neck bottle equipped with a thermometer, a constant pressure dropping funnel and mechanical stirring, stir well at room temperature, add anhydrous trichloromethane Aluminum chloride (123.5 g) and TEBA (triethylbenzyl ammonium chloride) (0.70 g) were stirred at room temperature until the solids were completely dissolved. Slowly and evenly add pyridine (170ml) dropwise at 0-5°C, slowly heat up to reflux (46-48°C), after reflux for 9 hours, the temperature drops below 10°C, adjust pH=2 (1000ml) with 20% hydrochloric acid, The starting material was recovered by extraction with methyl chloride (2×400ml), and the aqueous phase was extracted with ethyl acetate (3×500ml). The combined organic phases were dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and vacuum-dried...

Embodiment 2

[0019] Embodiment 2: Preparation of 3-hydroxyl-4-difluoromethoxybenzaldehyde

[0020]

[0021] Compound 2 (5.00g, 36.2mmol, 1.0eq) and n-butylammonium bromide (0.117g, 0.362mmol, 1%eq) were dissolved in isopropanol (60ml), stirred at room temperature for 20min, and 30% sodium hydroxide was added Solution (1.59g, 39.82mmol, 1.1eq), stirred at room temperature for 30min, slowly warmed up to 65°C, started to feed chlorodifluoromethane, kept the temperature at 60-65°C, added 30% sodium hydroxide ( 0.43g, 10.86mmol, 0.3eq), continue the reaction, add 30% sodium hydroxide solution (0.43g, 10.86mmol, 0.3eq) after another 1.5h, continue the reaction for 5-6h, drop the temperature to 15°C, add Water terminates the reaction. Filtrate to remove the solid residue, extract the filtrate with ethyl acetate, combine the organic phases, wash with water until neutral, dry over anhydrous sodium sulfate, evaporate the solvent, and perform silica gel column chromatography (petroleum ether: eth...

Embodiment 3

[0022] Embodiment 3: Preparation of 3-hydroxyl-4-difluoromethoxybenzaldehyde

[0023]

[0024] Compound 2 (5.00g, 36.2mmol, 1.0eq) and n-butylammonium bromide (0.117g, 0.362mmol, 1%eq) were dissolved in isopropanol (60ml), stirred at room temperature for 20min, and 30% sodium hydroxide was added Solution (1.59g, 39.82mmol, 1.1eq), stirred at room temperature for 30min, slowly warmed up to 65°C, started to feed chlorodifluoromethane, kept the temperature at 70-75°C, added 30% sodium hydroxide ( 0.43g, 10.86mmol, 0.3eq), continue the reaction, add 30% sodium hydroxide solution (0.43g, 10.86mmol, 0.3eq) after another 1.5h, continue the reaction for 5-6h, the temperature drops to 15°C, add Water terminates the reaction. Filtrate to remove the solid residue, extract the filtrate with ethyl acetate, combine the organic phases, wash with water until neutral, dry over anhydrous sodium sulfate, evaporate the solvent, and perform silica gel column chromatography (petroleum ether: et...

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Abstract

A disclosed preparation method of 4-difluoromethoxy-3-hydroxybenzaldehyde comprises the following steps: in an organic solvent, in the presence of a catalyst tetrabutylammonium bromide, under the effect of an acid binding agent, performing a nucleophilic substitution reaction on a compound 2 and difluorochloromethane, wherein the reaction temperature is 60-120 DEG C, and the organic solvent is one or more of isopropanol, DMF and 1, 4-dioxane. The preparation method is high in product yield and applicable to industrialized production.

Description

technical field [0001] The present invention specifically relates to a preparation method of 3-hydroxyl-4-difluoromethoxybenzaldehyde. Background technique [0002] 3-Hydroxy-4-difluoromethoxybenzaldehyde is an important intermediate for the preparation of phosphodiesterase 4 inhibitor roflumilast. The synthesis method of 3-hydroxy-4-difluoromethoxybenzaldehyde is usually prepared by reacting 3,4-dihydroxybenzaldehyde with a fluorinating agent. Since 3,4-dihydroxybenzaldehyde has two hydroxyl groups that can react with difluoromethyl, therefore, in addition to the required 4-OH monosubstituted product, there is also a by-product 3,4-difluoromethoxy Benzaldehyde (double substitution), generated. Due to the generation of double substitution, the yield of 4-OH monosubstituted product decreased. [0003] How to improve the yield of 4-OH mono-substitution, many patents have been reported. For example, in the patent document US2008 / 15226, sodium chlorodifluoroacetate is used a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C47/575C07C45/64
Inventor 肖旭华孙占莉袁博
Owner SHANGHAI INST OF PHARMA IND
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