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New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid

A technology of difluoromethoxybenzoic acid and cyclopropylmethoxy, which is applied in the preparation of carboxylate/lactone, organic chemistry, etc., can solve problems such as difficult industrial scale-up production, and achieve easy operation and low side reaction little effect

Inactive Publication Date: 2011-06-15
NANJING SIMCERE MEDICAL LAB CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Difficult to carry out industrial scale-up production

Method used

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  • New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid
  • New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid
  • New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid

Examples

Experimental program
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Embodiment 1

[0035] Example 1: 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

[0036] Step (1): Preparation of 3-nitro-4-difluoromethoxybenzoic acid methyl ester

[0037] 26.0g of methyl 3-nitro-4-hydroxybenzoate, 0.67g of benzyltrimethylammonium chloride, 31.4g of 50% sodium hydroxide and 200mL of dioxane were added to the reactor, and the Under stirring, chlorodifluoromethane was introduced into the system. After the reaction, ice water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 28.4 g of methyl 3-nitro-4-difluoromethoxybenzoate with a yield of 87 %.

[0038] Step (2): Preparation of 3-amino-4-difluoromethoxybenzoic acid methyl ester

[0039] 28.0 g of methyl 3-nitro-4-difluoromethoxybenzoate was dissolved in 500 mL of methanol, 2.8 g of 10% palladium carbon (containing 50% water) was added, and hydrogenated at normal pressure for 10 h. Palladium carbon was removed by filtration...

Embodiment 2

[0045] Example 2: 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

[0046] Step (1): Preparation of ethyl 3-nitro-4-difluoromethoxybenzoate

[0047] Add 35.0g of ethyl 3-nitro-4-hydroxybenzoate, 3.5g of tetrabutylammonium bromide, 65mL of 35% sodium hydroxide and 250mL of toluene into the reactor. into chlorodifluoromethane. After the reaction, ice water was added, the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 36.8 g of ethyl 3-nitro-4-difluoromethoxybenzoate with a yield of 85%. .

[0048] Step (2): Preparation of ethyl 3-amino-4-difluoromethoxybenzoate

[0049] 36.0 g of ethyl 3-nitro-4-difluoromethoxybenzoate was dissolved in 500 mL of glacial acetic acid, 63.0 g of iron powder was added in batches at room temperature, and stirred for another 3 h. Add 500mL of toluene, filter through celite, and concentrate the filtrate. The residue was dissolved in ethyl acetate, washed with ...

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Abstract

The invention relates to a new method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid. The method is characterized by taking 3-nitro-4-hydroxybenzoic acid ester as the raw material to obtain the 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid through alkylation, reduction, diazotization, hydrolysis, alkylation, deprotection and the like. The 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid is a key intermediate for synthesizing the drug roflumilast.

Description

technical field [0001] The present invention relates to a new method for synthesizing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is a synthetic drug The key intermediate of roflumilast. Background technique [0002] Roflumilast (Daxas) was jointly developed by Swiss Nycomed Company and American Forest Company, and was approved for marketing by the European Union on July 6, 2010, for the treatment of chronic obstructive pulmonary disease (COPD). Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor, which is a new class of COPD treatment drug approved by the European Union for the first time in more than ten years. Roflumilast is a once-a-day oral tablet that must be used in combination with other bronchodilators for the treatment of chronic bronchitis-associated severe COPD (diastolic FEV1 less than 50% of predicted value) in adult patients with a history of frequent exacerbations Maintenance treatment. ...

Claims

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Application Information

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IPC IPC(8): C07C51/09C07C65/26
Inventor 廖明毅李瑞杨少宁张连第丁磊
Owner NANJING SIMCERE MEDICAL LAB CO LTD
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