Method for preparing drug Roflumilast for treating chronic obstructive pulmonary disease

A technology for roflumilast and a drug, which is applied in the field of chemical drug synthesis, can solve problems such as difficult to obtain widely, expensive starting materials, difficult quantitative control, etc., so as to avoid the use of precious metal catalysts, shorten the synthesis process route, and reduce the The effect of production costs

Inactive Publication Date: 2017-05-10
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The limitations of this route are: low-temperature bromination is required, and the requirements for equipment are high; the gaseous difluoromethyl etherification reagent is used, which is highly toxic, and it is difficult to quantitatively control the amplification reaction, and there are many by-products; the use of noble metal Pd Catalytic carbonylation also uses highly toxic CO, which has high cost and poor industrial operability
[0012] The starting materials of this route are expensive and difficult to obtain widely; the synthetic route is long, the total yield is low, metal catalysts are used, and it is difficult to scale up the application
[0013] The limitations of the synthetic routes reported in the existing patent literature are: low-temperature bromination is required, and the requirements for equipment are high; gaseous difluoromethyl etherification reagents are used, which are highly toxic and difficult to quantitatively control during amplification reactions, and side effects are obtained. There are many products and the reaction selectivity is not high; the use of noble metal Pd to catalyze carbonylation also uses highly toxic CO, which is costly and poor in industrial operability

Method used

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  • Method for preparing drug Roflumilast for treating chronic obstructive pulmonary disease
  • Method for preparing drug Roflumilast for treating chronic obstructive pulmonary disease
  • Method for preparing drug Roflumilast for treating chronic obstructive pulmonary disease

Examples

Experimental program
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Effect test

example 1

[0036] Example 1: Preparation of 3-hydroxyl-4-difluoromethoxybenzoic acid methyl ester

[0037] N 2 Under protection, in a 250ml three-necked bottle, 10g (59.47mmol) 3,4-dihydroxybenzoic acid methyl ester, 8.93g (89.193mmol) KHCO 3 Dissolve in 150ml DMF. Stir and slowly heat to 80°C. ClF 2 9.07g (59.47mmol) of COONa was dissolved in 60ml of DMF and added dropwise to the above reaction system. After the addition was complete, the reaction was carried out at this temperature for 6h. After cooling to room temperature, 400ml of water was added, the organic phase was extracted with 150ml of ethyl acetate x 3, and the combined organic phase was dried over anhydrous sodium sulfate. After distilling off the solvent, 7.01 g of the crude product was obtained, with a yield of 53.95%.

example 2

[0038] Example 2: Preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid methyl ester

[0039] Put 5g (22.92mmol) of methyl 3-hydroxy-4-difluoromethoxybenzoate and 8.80g (63.67mmol) of anhydrous potassium carbonate in a 250ml three-necked bottle, add 130ml of DMF to dissolve the substrate, and stir at room temperature 30min. Add 4.3g (31.85mmol) of cyclopropyl bromide in 10ml of DMF dropwise to the reaction system, and then heat to 75°C for 10h after the dropwise addition. After the reaction is completed, cool to room temperature, add 300ml of water, adjust the pH to 8-9, extract with ethyl acetate 150ml×3, combine the organic phases, and dry over anhydrous sodium sulfate. After distilling off the solvent, the crude product was recrystallized from ethyl acetate to obtain 5.82 g of a white solid, with a yield of 93.27%.

example 3

[0040] Example 3: Preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid

[0041] Dissolve 5g (18.37mmol) of methyl 3-cyclopropylmethoxy-4-difluoromethoxybenzoate in 50ml of methanol, slowly add 10ml of 30% NaOH (aq) dropwise under ice-bath conditions, dropwise After completion, react at 20-30°C for 2h. After the reaction was completed, the pH was adjusted to 4 with concentrated hydrochloric acid, extracted with 100 ml×3 ethyl acetate, the organic phase was collected, and dried by adding anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 4.6 g of the target product was obtained as a white solid, with a yield of 99%.

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Abstract

The invention relates to a method for preparing a drug Roflumilast for treating the chronic obstructive pulmonary disease. The Chinese chemical name of the drug Roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. According to the method, in a process route, a dihydroxyl-substituted benzoate derivative, which can be extensively obtained, is adopted as a starting raw material, so that the consumption of noble metal catalysts is avoided, the synthesis process route is shortened, and the production cost is reduced greatly; through introducing difluoromethoxy by replacing a gaseous reagent with a solid difluoromethyl etherification reagent, which is safe, efficient, cheap and readily available, side reactions are reduced, and the selectivity of the reaction is improved; and the target product is obtained efficiently through condensing carboxyl groups and amino groups.

Description

technical field [0001] The invention relates to a new synthesis method of Roflumilast, a drug for treating chronic obstructive pneumonia. It belongs to the field of chemical drug synthesis. Background technique [0002] Roflumilast (Daxas) is the first phosphodiesterase-4 (PDE4) inhibitor produced and marketed by Forest Pharmaceuticals, a subsidiary of Forest Lab, and was approved by the European Union and the United States on July 6, 2010 and 2011 respectively Approved on February 24 for the treatment of chronic obstructive pulmonary disease (COPD). This medicine is indicated for the treatment of cough and phlegm caused by bronchitis in patients with severe COPD. [0003] From the current literature, the synthetic route of Roflumil mainly has the following three methods: [0004] (1) The synthetic route reported in US6822114 and WO2004033430 patents is: using catechol as raw material, through O-alkylation, bromination, O-alkylation, carbonylation, acylation and other rea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 吴德志李建高赵玉燕张振支永刚
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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