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Preparation method of 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 great positive progress , easy to operate, great effect of practical application value

Active Publication Date: 2012-08-01
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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  • Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid
  • Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid
  • Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] 3-Cyclopropylmethoxy-4-iodobenzaldehyde

[0065] 24.8 g of 3-hydroxy-4-iodobenzaldehyde, 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 500 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 30.1 g of 3-cyclopropylmethoxy-4-iodobenzaldehyde with a yield of 99%.

[0066] 1 H NMR (CDCl 3 ): δ0.40-0.47(m, 2H), 0.63-0.71(m, 2H), 1.23-1.40(m, 1H), 3.97(d, 2H), 7.38(d, 1H), 7.42(s, 1H ), 7.87 (d, 1H), 9.94 (s, 1H).

Embodiment 2

[0068] 3-Cyclopropylmethoxy-4-hydroxybenzaldehyde (4)

[0069] 1.9 g of cuprous iodide, 2.9 g of 8-hydroxypyridine, 100 mL of DMSO, and 30.1 g of methyl 3-cyclopropylmethoxy-4-iodobenzoate were added to the reactor. Under further stirring, 100 mL of a 25% potassium hydroxide aqueous solution was added.

[0070] 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 17.8 g of 3-cyclopropylmethoxy-4-hydroxybenzaldehyde with a yield of 93%.

[0071] 1 H NMR (CDCl 3 ): δ0.37-0.41(m, 2H), 0.65-0.77(m, 2H), 1.25-1.40(m, 1H), 3.98(d, 2H), 7.00(d, 1H), 7.63(s, 1H ), 7.77(d, 1H), 10.2(s, 1H).

Embodiment 3

[0073] 3-Cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (5)

[0074] Add 26.0g of potassium carbonate to a 100mL reactor containing DMF, raise the temperature to 80°C, and add 17.9g of 3-cyclopropylmethoxy-4-hydroxybenzaldehyde and 1-chloro-1,1-difluoro A solution of 28.4 g of sodium acetate in 50 mL of DMF was added and reacted for 2 hours. Cool down to room temperature, add 300 g of water to dilute, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 22.1 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde , yield 98%.

[0075] 1 H NMR (CDCl 3 ): δ0.38-0.41(m, 2H), 0.64-0.69(m, 2H), 1.28-1.32(m, 1H), 3.95(d, 2H), 6.72(t, 1H), 7.22(d, 1H ), 7.55 (s, 1H), 7.68 (d, 1H), 10.1 (s, 1H).

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Abstract

The invention discloses a preparation method of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. The preparation method includes the following steps of subjecting 3-hydroxyl -4-halogenated benzaldehyde represented as formula (2) to alkylation to obtain a compound represented as formula (3); subjecting the compound represented as the formula (3) to hydroxylation to obtain a compound represented as formula (4); subjecting the compound represented as the formula (4) to alkylation to obtain a compound represented as formula (5); and subjecting the compound represented as the formula (5) to oxidation to obtain the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (1). According to the preparation method, the preparation method is easy and convenient to operate, reaction yield of each step is high, intermediates are easy to purify, reported defects of preparation methods of the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid serving as the key intermediate of roflumilast are overcome, great progressive effects and practical application value are achieved, and besides, the preparation method is mostly beneficial for industrial production. The reaction general formula is shown as follows.

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 drug. Background technique [0002] Roflumilast (Daxas) was developed by Nycomed, Switzerland, and was approved by the European Union in June 2010 for severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis. And in February 2011, it was approved by the US FDA for the treatment of severe chronic obstructive pulmonary disease (COPD), with the trade name 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 wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C65/26C07C51/16
Inventor 李建其倪峰黄雷王佳静黄美花左学民蒋巍潘伟
Owner SHANXI C&Y PHARMACEUTICAL GROUP CO LTD
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