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High-bioavailability roflumilast compound

A technology for roflumilast and compounds is applied in the field of roflumilast compounds and their preparation, which can solve the problems of high total amount of impurities, low bioavailability, low optical purity and the like, and achieves less side reactions, simple operation and easy operation. The effect of purification

Active Publication Date: 2012-02-15
TIANJIN HANKANG PHARMA BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second generation of selective PDE-4 inhibitors, such as cilomilast and roflumilast, but the results of some trials of cilomilast are different from expectations in terms of drug efficacy and safety. As a result, further development of the drug has been discontinued
Although the previous yields are considerable and the treatment is convenient, the final step uses expensive difluoroxenon, the purification is firstly passed through a silica gel column, and then purified on HPLC to obtain qualified products, which makes it difficult to be used in industry. mass production
[0023] During the research process, the method of the above patent literature was repeated to obtain roflumilast in various crystalline or non-crystalline forms, the total amount of impurities was high, the optical purity was low, and the bioavailability was low

Method used

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  • High-bioavailability roflumilast compound
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  • High-bioavailability roflumilast compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] step 1

[0075] Add 50g of p-hydroxybenzonitrile, 1.2g of benzyltrimethylammonium chloride, 99g of potassium carbonate and 500 mL of acetone into the reaction flask, and feed chlorodifluoromethane into the system under stirring. After the reaction was complete, ice water was added, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and spin-dried to obtain 67.5 g of 4-difluoromethoxybenzonitrile with a yield of 95%.

[0076] step 2

[0077] 20 m of 40% nitric acid and 67 g of 4-difluoromethoxybenzonitrile were mixed and reacted at 40 °C for 0.5 h. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, dried over sodium sulfate, filtered, and spin-dried to obtain 76.4 g of 3-nitro-4-difluoromethoxybenzonitrile, yield 90%.

[0078] step 3

[0079] Add 6 g of 10% Pd / C (containing 50% water), 76 g of 3-nitro4-difluoromethoxybenzonitrile, and 500 mL of methanol into the r...

Embodiment 2

[0092] Take the raw material of roflumilast in Example 1, pack it in a medicinal composite film, place it at 40°C±2°C with a relative humidity of 75%±5% constant temperature and humidity, and take samples for testing in 0, 1, 2, 3, and 6 months respectively , the test results are shown in the table

[0093]

[0094] The above results show that the quality of roflumilast is stable.

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a roflumilast compound shown in formula I and a preparation method thereof. Roflumilast is a new crystal form, and has the advantages that the chemical purity is high, the highest purity content is smaller than 1 per mill, the optical purity is high, roflumilast is soluble in water, and a preparation prepared from roflumilast has good stability, particularly wet stability, and high bioavailability. The compound provided by the invention has low production cost and stable quality, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a roflumilast compound and a preparation method thereof. Background technique [0002] There are approximately 42 million asthmatics and 28 million COPD (chronic obstructive pulmonary disease) patients worldwide. In the past ten years, with the global air pollution and environmental deterioration, the morbidity and mortality of asthma are on the rise, and more than 180,000 people die from asthma every year. Another analysis shows that by 2020, COPD will climb from the current sixth place in the global cause of death to the third place. It is conservatively estimated that the number of deaths due to COPD will reach more than 3.5 million worldwide by then. In China, an epidemiological survey conducted by Academician Zhong Nanshan showed that the overall prevalence of COPD in China is 8.2%, of which 12.4% are male and 5.1% are female. There are more than 40 million C...

Claims

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Application Information

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IPC IPC(8): C07D213/76A61K31/44A61P11/00A61P11/06A61P29/00
Inventor 严洁黄欣
Owner TIANJIN HANKANG PHARMA BIOTECH
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