Method for synthesizing roflumilast intermediate

A synthetic method, the technology of roflumilast, applied in the field of medicine and chemical industry, can solve the problems of harsh process conditions, low yield, high cost of raw materials, etc., and achieve the effect of cheap and easy-to-obtain raw materials, simple process principle, and high yield

Active Publication Date: 2014-01-15
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In order to solve the problems of poor selectivity, low yield, high cost of raw materials and harsh process conditions in the production process of the existing roflumilast intermediate 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, the present invention provides A kind of synthetic method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

Method used

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  • Method for synthesizing roflumilast intermediate
  • Method for synthesizing roflumilast intermediate
  • Method for synthesizing roflumilast intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Synthesis of 1,2-bis(difluoromethoxy)benzene (compound 2):

[0048] Add 11.0 g (100 mmol) of catechol and 110 ml of DMF to the reaction flask, add 5.1 g (210 mmol) of sodium hydride in batches under stirring, raise the temperature to 80°C, and pass through chlorodifluoromethane to keep the reaction for 8 h. TLC monitored the complete conversion of the reactant to the product (developing solvent: ethyl acetate: n-hexane = 1:3). After the reaction was completed, the solvent DMF was recovered under reduced pressure. After cooling to room temperature, about 200 mL of water was added, and 80 ml of dichloromethane was added to extract three times. Dry over magnesium sulfate, filter out the desiccant, and concentrate under reduced pressure until there is no slip-out product to obtain 17.2 g of oily substance, with a yield of 82%, which is directly used in the next reaction without purification. ESI-MS (m / z ) : 211 [M+1] + .

[0049] Synthesis of 3,4-bis(difluoromethoxy)benz...

Embodiment 2

[0059] Synthesis of 1,2-bis(difluoromethoxy)benzene (compound 2)

[0060] Add 11.0 g (100 mmol) of catechol and 80 ml of DMF to the reaction flask, add 11.4 g (220 mmol) of sodium ethoxide in batches under stirring, heat to 80°C, pass through chlorodifluoromethane, and react for 12 h. TLC monitored the complete conversion of the reactant to the product (developing solvent: ethyl acetate: n-hexane = 1:3). Most of the DMF was recovered by distillation. After cooling to room temperature, add about 200 mL of water, add 80 ml of dichloromethane to extract three times, combine the organic layers, wash with 100 ml of 5% NaOH, wash twice with 100 ml of water until neutral, and dry with 18 g of anhydrous magnesium sulfate. Filter off the desiccant, concentrate under reduced pressure until there is no slip-out, and obtain 16.8 g of oil, with a yield of 80%, which is directly used in the next reaction without purification.

[0061] Synthesis of 3,4-bis(difluoromethoxy)benzaldehyde (comp...

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Abstract

The invention discloses a method for synthesizing 3-cyclopropyl methoxyl-4difluoro methoxybenzoic acid, which can be used as an important intermediate for preparing roflumilast. 3-cyclopropyl methoxyl-4difluoro methoxybenzoic acid can be prepared by using pyrocatechin as an initial raw material, performing substitution reaction and Velsmeier reaction, selectively removing difluoro methyl, and carrying out alkylation and oxidation reaction. The method has advantages of cheap and easily available raw material, good reaction selectivity, high yield, and stable finished product quality.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, and more specifically relates to a synthetic method for preparing roflumilast key intermediate 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. Background technique [0002] Roflumilast is a new drug for the treatment of chronic obstructive pulmonary disease (COPD), which belongs to the phosphodiesterase-4 (PDE-4) inhibitor, and is a new class of COPD treatment drug approved by the European Union for the first time in more than ten years. Indicated for cough in patients with severe COPD and symptoms of excess mucus associated with bronchitis. [0003] The Chinese chemical name of roflumilast is: N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, and its structural formula is as follows: [0004] [0005] The chemical synthesis processes of roflumilast that have been reported are as follows: [0006] Patent WO9501338 discloses the synthesis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C65/26C07C51/285C07C51/16
CPCC07C41/16C07C45/00C07C45/673C07C45/71C07C51/16C07C51/285C07C2601/02C07C65/26C07C47/575C07C43/225
Inventor 李子清贾春荣王宗玉
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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