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A kind of preparation method of Roflumilast intermediate for treating chronic obstructive pulmonary disease

A technology of roflumilast and an intermediate, which is applied in the field of drug synthesis, can solve the problems of many impurities, many by-products, difficult industrial production and the like, and achieves the effects of wide source of raw materials and energy saving

Active Publication Date: 2016-07-13
GUANGDONG YIMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The method has short steps, but the first step of the selective alkylation reaction has many by-products and is not easy to separate, and the yield is 20-30%, resulting in many impurities and high synthesis costs, making it difficult to carry out industrial production

Method used

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  • A kind of preparation method of Roflumilast intermediate for treating chronic obstructive pulmonary disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1: 3, the preparation of 4-two (cyclopropylmethoxy) methyl benzoate

[0021] Referring to the method of WO2005 / 026095: add 50.2 g of bromomethylcyclopropane to 350 mL of acetone containing 50 g of methyl 3,4-dihydroxybenzoate and 82.1 g of potassium carbonate, and heat the suspension to 40°C for 16 hours. Filtration and concentration, the crude product was passed through a silica gel column (eluent 5% ethyl acetate n-hexane) to obtain 10.5 g of 3,4-bis(cyclopropylmethoxy)methyl benzoate and 3-cyclopropylmethoxy - 15.8 g of methyl 4-hydroxybenzoate. Methyl 3,4-dicyclopropylmethoxybenzoate 1 HNMR (400MHz, CDCl3) δ0.33-0.35(m,2H); 0.53-0.55(m,2H); 1.19-1.22(m,1H); 1.23-1.26(m,1H); 3.84(s,3H) ; 3.83-3.89 (m, 4H); 6.99-7.05 (m, 1H); 7.40-7.42 (d, 1H); 7.50-7.52 (d, 1H).

Embodiment 2

[0023] Preparation of methyl 3-cyclopropylmethoxy-4-hydroxybenzoate

[0024] Weigh 2.76g (10mmol) of methyl 3,4-bis(cyclopropylmethoxy)benzoate, add 20mL of DMF to dissolve, add 1.01g (12mmol) of sodium ethanethiolate, stir the solution, and heat to 85°C for reaction 6 After hours, TLC monitored the reaction (ethyl acetate:n-hexane=1:4). After completion, 50 mL of water was added, extracted with ethyl acetate (50 mL×3), washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed to obtain 1.96 g of a white solid with a yield of 88.5% and a melting point of 48.3-49.5°C. 1 HNMR (400MHz, CDCl3) δ0.40-0.31 (m, 2H); 0.71-0.61 (m, 2H); 1.35-1.22 (m, 1H); 3.87 (s, 3H); 3.90 (d, J = 6.8Hz ,2H); 6.16(s,1H); 6.90(d,1H); 7.52(d,1H); 7.60(m,1H).

[0025] Synthesis of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

[0026] Add 2.22g (10mmol) of methyl 3-cyclopropylmethoxy-4-hydroxybenzoate and 2.1g (15mmol) of anhydrous potassium carbon...

Embodiment 3

[0027] Embodiment 3: Preparation of 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester

[0028] Weigh 2.76g (10mmol) of methyl 3,4-bis(cyclopropylmethoxy)benzoate, add 20mL of DMSO to dissolve, add 1.01g of sodium ethanethiolate, stir the solution, heat to 90°C for 6 hours, TLC Monitor the reaction (ethyl acetate:n-hexane=1:4). After completion, add 50 mL of water, extract with ethyl acetate (50 mL×3), wash with saturated brine, dry over anhydrous magnesium sulfate, filter, and remove the solvent. 1.80 g of white solid was obtained with a yield of 81.1%.

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a preparation method of an intermediate of an anti-asthma medicine of roflumilast. According to the method, an impurity compound 3,4-2(Cyclopropylmethoxy) methyl benzoate generated during a roflumilast production process is used as a feedstock in a polar solvent, and with existence of an ether removal reagent, cyclopropylmethyl is selectively removed to generate 3-cyclopropylmethoxyl-4-dihydroxybenzoic ester; and after reaction between 3-cyclopropylmethoxyl-4-dihydroxybenzoic ester and chlorodifluoromethane, 3-cyclopropylmethoxyl-4-difluoromethoxybenzoic acid is obtained through hydrolysis. According to the invention, wastes are changed into useful materials; energy is saved; and preparation of roflumilast is provided with more extensive feedstock sources.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for preparing an intermediate of roflumilast, a medicine for treating chronic obstructive pulmonary disease. Background technique [0002] Roflumilast (roflumilast), the chemical name is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, a German Altana The phosphodiesterase 4 (PDE4) inhibitor developed by the company was approved in Europe in July 2010, and was subsequently launched in Germany, the United Kingdom and Spain. It is clinically used for the treatment of chronic obstructive pulmonary disease (COPD), with the trade name Daxas, launched in 2011 In March, it was approved for marketing by the US FDA. This product can reduce the release of inflammatory mediators by inhibiting PDE4, thereby inhibiting the damage to lung tissue caused by respiratory diseases such as COPD and asthma. [0003] There are many synthetic routes of roflumilast, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C65/26C07C27/02
CPCC07C51/09C07C67/31C07C67/327C07C65/26C07C69/92
Inventor 张雪岷侯明月陈海清
Owner GUANGDONG YIMING PHARMA