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Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

A technology of difluoromethoxybenzoic acid and cyclopropylmethoxy, which is applied in the field of preparation of the chronic obstructive pulmonary disease drug roflumilast, can solve problems such as difficult industrial scale-up production, and achieve simple and large-scale production. The effect of practical application value

Active Publication Date: 2014-02-26
SHANXI C&Y PHARMACEUTICAL GROUP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above preparation method is difficult to carry out industrial scale-up production

Method used

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  • Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid
  • Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid
  • Method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Methyl 3-cyclopropylmethoxy-4-iodobenzoate

[0075] 27.8 g of methyl 3-hydroxy-4-iodobenzoate, 27.6 g of potassium carbonate, 20.3 g of bromomethylcyclopropane, and 150 mL of DMF were stirred at 70° C. for 3 hours. After the reaction was diluted with 450 g of water, it was extracted with ethyl acetate, washed with water, and the organic layer was separated, washed with water, and dried. The solvent was distilled off under reduced pressure to obtain 32.9 g of methyl 3-cyclopropylmethoxy-4-iodobenzoate with a yield of 99%.

[0076] 1 H NMR (CDCl 3 ): δ0.42-0.48(m, 2H), 0.64-0.71(m, 2H), 1.25-1.45(m, 1H), 3.93(s, 3H), 3.98(d, 2H), 7.38(d, 1H ), 7.42(s, 1H), 7.87(d, 1H).

Embodiment 2

[0078] 3-Cyclopropylmethoxy-4-hydroxybenzoic acid (4)

[0079] Add 1.9 g of cuprous iodide, 2.9 g of 8-hydroxypyridine, 100 mL of DMSO and 32.9 g of methyl 3-cyclopropylmethoxy-4-iodobenzoate obtained in Example 1 into the reactor. With further stirring, 100 mL of 25% potassium hydroxide aqueous solution was added. Heated to 100°C for 24 hours, cooled to room temperature and filtered to remove the copper catalyst. Adjust to acidity with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 19.6 g of 3-cyclopropylmethoxy-4-hydroxybenzoic acid with a yield of 95%.

[0080] 1 H NMR (CDCl 3 ): δ0.37-0.40(m, 2H), 0.62-0.77(m, 2H), 1.23-1.40(m, 1H), 3.97(d, 2H), 7.00(d, 1H), 7.63(s, 1H ), 7.75 (d, 1H), 12.1 (br, 1H).

Embodiment 3

[0082] Methyl 3-cyclopropylmethoxy-4-hydroxybenzoate

[0083] Add 19.6 g of 3-cyclopropylmethoxy-4-hydroxybenzoic acid obtained in Example 2 and 200 mL of methanol into the reactor, stir and cool to 0°C. Slowly added 22.4 g of thionyl chloride dropwise, stirred and slowly raised to room temperature, and then heated to reflux for 3 hours. The solvent was evaporated to dryness to obtain 20.9 g of methyl 3-cyclopropylmethoxy-4-hydroxybenzoate with a yield of 99%.

[0084] 1 H NMR (CDCl 3 ): δ0.38-0.41(m, 2H), 0.64-0.77(m, 2H), 1.23-1.43(m, 1H), 3.94(s, 1H), 3.97(d, 2H), 7.09(d, 1H ), 7.63 (s, 1H), 7.70 (d, 1H).

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Abstract

The invention discloses a method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. The method comprises the following steps of: performing alkylation on 3-hydroxy-4-halogenated benzoate shown as a formula (2) to obtain a compound of a formula (3); performing hydroxylation on the compound of the formula (3) to obtain a compound of a formula (4); performing esterification on the compound of the formula (4) to obtain a compound of a formula (5); performing alkylation on the compound of the formula (5) to obtain a compound of a formula (6); and hydrolyzing the compound of the formula (6), and thus obtaining the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (1). The method is easy and convenient to operate, the reaction yield in each step is high, and intermediates are easy to purify. The method overcomes the defects of the reported method for preparing Roflumilast key intermediate 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and has great positive progress effects and practical application value. Moreover, the invention has the greatest advantage that the method is suitable for industrialized production. The reaction general formula is shown in the specification.

Description

technical field [0001] The invention relates to a method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, which is used in the preparation of roflumilast, a chronic obstructive pulmonary disease medicine. Background technique [0002] Roflumilast (Daxas) was developed by Nycomed, Switzerland, and was approved by the European Union for severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis in June 2010, and was approved by the US FDA in February 2011 For the treatment of severe chronic obstructive pulmonary disease (COPD), the trade name is Daliresp. Roflumilast, an oral, selective phosphodiesterase 4 (PDE4) inhibitor, has been shown to treat chronic obstructive pulmonary disease (COPD) in a novel mode of action, the first to be approved in more than a decade. A new class of drugs for the treatment of COPD approved by the European Union. Roflumilast is a once-a-day oral tablet for the maintenance treatment of severe COPD associated with ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C65/21C07C27/02
Inventor 李建其倪峰朱皓阳苏温柔左学民潘伟蒋巍
Owner SHANXI C&Y PHARMACEUTICAL GROUP CO LTD
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