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Preparation method of roflumilast intermediate 3-cyclopropyl methoxyl-4-(difluoromethoxy)benzoic acid

A technology of difluoromethoxybenzoic acid and cyclopropylmethoxybenzoic acid is applied in the field of preparing roflumilast intermediate 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, which can solve the problem of The reaction economy is poor, the diazotization reaction is not easy to control, and there are no problems such as providing a synthetic method for 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde, which achieves the effects of few synthetic route steps, convenient separation and little pollution.

Inactive Publication Date: 2014-12-03
贵州华瑞德医药科技有限公司 +1
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Problems solved by technology

The diazotization reaction adopted in this route is not easy to control and easily generates impurities
[0016] 5. CN102336703, this patent mainly uses new reaction conditions to oxidize 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde to acid, and improves 3-cyclopropylmethoxy-4- Condensation conditions of difluoromethoxybenzoic acid and 4-amino-3,5-dichloropyridine, without providing a specific synthesis method for 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde
This route has undergone multiple esterification and hydrolysis, and ligands are required to participate in the conversion of substituents at the 4-position, and the reaction economy is poor

Method used

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  • Preparation method of roflumilast intermediate 3-cyclopropyl methoxyl-4-(difluoromethoxy)benzoic acid
  • Preparation method of roflumilast intermediate 3-cyclopropyl methoxyl-4-(difluoromethoxy)benzoic acid
  • Preparation method of roflumilast intermediate 3-cyclopropyl methoxyl-4-(difluoromethoxy)benzoic acid

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Embodiment Construction

[0037] In order to make the technical means, creative features, work flow, and use method of the present invention easy to understand and understand the purpose and effect of the present invention, the present invention will be further described with reference to specific embodiments.

[0038] 1. Preparation of 4-benzyloxy-3-cyclopropylmethoxybenzaldehyde (III)

[0039] 4-benzyloxy-3-hydroxybenzaldehyde (II) (prepared according to the document Bioorg.Med.Chem.11 (2003), 4693-4711) 16g, anhydrous potassium carbonate 17.5g were added to 70mL anhydrous N, N -To dimethylformamide, add 14.2 g of bromomethylcyclopropane with stirring, increase the temperature to 80° C., and stir for reaction for 2 hours. After cooling, the reaction solution was poured into 300 mL of water, extracted with 2×300 mL of ethyl acetate, and the organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 19.2 g of white solid ...

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Abstract

The invention discloses a preparation method of roflumilast intermediate 3-cyclopropyl methoxyl-4-(difluoromethoxy)benzoic acid. A raw material of 3-hydroxy-4-benzyloxy benzaldehyde is subjected to 3-hydroxy cyclopropane methylation to convert aldehyde group to methyl carboxylate; then the material is subjected to catalytic hydrogenation to remove 4-benzyl group and subjected to difluoro methoxylation; and then the reaction product is hydrolyzed to obtain the 3-cyclopropyl methoxyl-4-(difluoromethoxy)benzoic acid. The method has the advantages of simple operation, mild reaction conditions and high regioselectivity, and is suitable for industrialized production.

Description

Technical field [0001] The present invention relates to the field of medical chemistry synthesis, in particular to a method for preparing roflumilast intermediate 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. Background technique [0002] Roflumilast is a new oral drug developed by Nycomed to treat asthma and chronic obstructive pulmonary disease. It was approved in the European Union in July 2010 for use as an auxiliary bronchodilator maintenance treatment for patients with severe chronic obstructive pulmonary disease. It became the first new oral drug approved for the treatment of chronic obstructive pulmonary disease worldwide in more than a decade. Roflumilast is a phosphodiesterase 4 inhibitor, which can specifically act on certain enzymes involved in smooth muscle contraction, thereby blocking the signal transmission of pro-inflammatory response, has anti-inflammatory activity, and is used in the clinical treatment of asthma and COPD Obtained a better curative effect...

Claims

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Application Information

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IPC IPC(8): C07C65/26C07C51/09
CPCC07C45/71C07C51/09C07C67/307C07C67/31C07C67/44C07C2601/02C07C47/575C07C69/92C07C65/26
Inventor 张翔尹大力程潜
Owner 贵州华瑞德医药科技有限公司
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