Vilanterol intermediate as well as preparation method and application thereof
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A technology of intermediates and compounds, applied in the field of vilanterol intermediates and its preparation, can solve the problems of difficult control of the quality of intermediates and finished products, inaccurate measurement of oily substances, unfavorable industrial production, etc., to achieve good quality and easy operation , high product yield and high purity
Pending Publication Date: 2021-07-16
TIANJIN PHARMA GROUP CORP
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[0013] From above-mentioned 3 kinds of synthetic methods, all need to go through intermediate formula II compound, and formula II compound is an oily substance, so to obtain vilanterol, it is unavoidable that the last step intermediate formula II compound is the implementation of oily substance
This intermediate is the closest to the finished product, and it is an oily substance that has many disadvantages, such as column chromatography purification methods that require cumbersome operations and poor reproducibility; in terms of analysis and detection, due to inaccurate measurement of oily substances, the content is difficult to determine
These disadvantages make it difficult to control the quality of intermediates and finished products, which is not conducive to industrial production
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Embodiment 1-1
[0058] Add 40 mL of ethyl acetate, 2.9 g of triphenylacetic acid and 5.5 g of the compound of formula II to the reaction flask, stir the reaction at 70 ° C, after the reaction is completed, drop to 25 ° C for crystallization for 2 h, then crystallize at 5 ° C for 2 h, filter to obtain The white solid was 7.7 g, the yield was 94.5%, and the HPLC purity was 99.2%.
[0059] The white solid obtained in Example 1-1 was subjected to X-ray powder diffraction measurement, and the measured characteristic peak positions were 2θ=5.3°, 7.8°, 12.4°, 13.8°, 14.1°, 15.0°, 16.0°, 16.3°, 18.2 °, 18.9°, 19.6°, 20.5°, 21.1°, 21.4°, 22.9°, 23.6°, 23.8°, 25.7°, 26.1°, 28.3°, such as figure 1 shown.
Embodiment 1-2
[0061] Add 30mL of ethanol, 2.9g of triphenylacetic acid and 5.5g of the compound of formula II to the reaction flask, stir the reaction at 65°C, after the reaction is completed, drop to 30°C for crystallization for 3h, then crystallize at 0°C for 1.5h, filter to obtain white The solid was 7.5 g, the yield was 92.0%, and the HPLC purity was 99.5%.
Embodiment 1-3
[0063] Add 60mL of methanol, 2.9g of triphenylacetic acid and 5.5g of the compound of formula II to the reaction bottle, stir the reaction at 60°C, and then drop to 20°C for 1.5h of crystallization after the reaction, then crystallize at 10°C for 3h, filter to obtain white The solid was 7.5 g, the yield was 92.0, and the HPLC purity was 99.4%.
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Abstract
The invention provides a vilanterol intermediate as well as a preparation method and application thereof, and relates to the technical field of chemical synthesis. According to the vilanterol intermediate, the compound shown in the formula I is salt of the compound shown in the formula II, the solid compound shown in the formula I is obtained from the oily compound shown in the formula II, the purity reaches up to 99.0% or above, when the compound shown in the formula I is used for preparing vilanterol and pharmaceutically acceptable salt thereof, purification through tedious separation methods such as column chromatography is not needed, materials are easy to measure accurately, the quality control of the vilanterol intermediate is facilitated, various defects caused by the fact that the compound shown in the formula II is an oily substance are effectively overcome, and the quality of vilanterol and pharmaceutically acceptable salt thereof can be better guaranteed.
Description
technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a vilanterol intermediate and its preparation method and application. Background technique [0002] β2-adrenergic receptor agonists are the most widely used drugs in the treatment of asthma and chronic obstructive pulmonary disease. The longest duration of action of β2-adrenoceptor agonists currently available on the market is 12 hours, which leads to the need for twice-daily dosing. In the past ten years, the development of β2-adrenoceptor agonists with high potency, high selectivity, fast onset, long duration of action, and once-a-day administration has attracted great attention from the pharmaceutical industry. Vilanterol triphenylacetate is a new type of ultra-long-acting β2-adrenoceptor agonist developed by Glaxo Group Co., Ltd., which has bronchodilation effect. [0003] The chemical name for vilanterol triphenylacetate is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)...
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