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Novel method for synthesizing umeclidinium bromide

A technology of umeclidinium bromide and a synthetic method, which is applied in the field of pharmaceutical synthesis technology, can solve the problems of restricting the scale-up production of umeclidinium bromide, poor safety, and unresolved problems, so as to achieve improved reaction efficiency and yield, low cost, and high reaction efficiency. The effect of short steps

Active Publication Date: 2018-09-21
成都伊诺达博医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

while failing to address the use of phenyllithium
[0019] It can be seen that in order to obtain the key intermediate α,α-diphenyl-1-azabicyclo[2.2.2]octane-4-methanol (compound 3), it is inevitable to use unstable and toxic benzene Lithium-based has the disadvantages of high cost, serious pollution, and poor safety, which restrict the scale-up production of umeclidinium bromide, so it is necessary to find a more environmentally friendly and operable synthetic method

Method used

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  • Novel method for synthesizing umeclidinium bromide
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  • Novel method for synthesizing umeclidinium bromide

Examples

Experimental program
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Effect test

Embodiment 1

[0043] Example 1 Preparation of 4-bromoquinuclidine Compound 5 was prepared from quinuclidin-4-ol (purchased from Hubei Wonder Chemical Co., Ltd.) by halogen substitution.

[0044] Add quinuclidin-4-ol (31.8 g, 0.25 mol) and phosphorus oxybromide (215 g, 0.75 mol) into the reaction flask, and raise the temperature to 80-90° C. for 4 h. Cool to 30-40°C, slowly pour the reaction solution into ice water, then add 10% aqueous sodium bicarbonate to adjust the pH value to 8-9, extract the product (200ml × 3) with dichloromethane, combine the organic phases, and use Washed with tap water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness and then distilled under reduced pressure to obtain 38.3 g of oil (4-bromoquinuclidine), with a yield of 80.6%.

Embodiment 2

[0045] The preparation of embodiment 2 4-bromoquinucidine

[0046] Quinuclidin-4-ol (31.8 g, 0.25 mol) and 47% hydrobromic acid (500 ml) were added into the reaction flask, and the temperature was raised to reflux for 5 h. Cool to room temperature, add 10% aqueous sodium bicarbonate solution to adjust the pH value to 8-9, extract the product (200ml×3) with dichloromethane, combine the organic phases, wash with tap water, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness and then distilled under reduced pressure to obtain 40.1 g of oil (4-bromoquinuclidine), with a yield of 84.4%.

Embodiment 3

[0047] Example 3 Preparation of α,α-diphenyl-1-azabicyclo[2.2.2]octane-4-methanol

[0048] Add 4-bromoquinuclidine (38g, 0.200mol) and anhydrous tetrahydrofuran (400ml) into the reaction flask, start stirring, then add magnesium chips (10.7g, 0.440mol) and 1g iodine, and stir the reaction at room temperature under nitrogen protection 2h. Control the temperature below 10°C, add diphenyl ketone (40.1 g, 0.220 mol) in anhydrous tetrahydrofuran solution (100 ml) dropwise, after the drop is complete, naturally warm to room temperature and stir for 3 h, and monitor the completion of the reaction by TLC. Slowly pour the reaction solution into 250ml of saturated ammonium chloride solution to quench, separate the layers, extract the organic phase with 1N hydrochloric acid (200ml), combine the aqueous phases, add saturated potassium carbonate solution to adjust the pH to >9, and precipitate a solid. Filtration, the filter cake was washed with ethyl acetate (100ml), and after drying, 53...

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Abstract

The invention discloses a method for preparing an umeclidinium bromide intermediate compound as shown in a formula 3, and further discloses a synthesizing method of umeclidinium bromide. The synthesizing method effectively avoids unstable phenyl lithium with high price and toxicity, corresponding quinuclidine building reaction steps are omitted, reaction steps are greatly decreased, and reaction efficiency and yield are improved. The synthesizing method is shorter in reaction step, mild in operation condition, high in safety, low in environmental pollution and higher in yield, and a good basisis provided for industrial amplification of the umeclidinium bromide.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, and in particular relates to a new route for synthesizing umeclidinium bromide (Umeclidinium). Background technique [0002] Chronic obstructive pulmonary disease (COPD) is characterized by incomplete airflow limitation and progressive aggravation, and has become the fifth leading cause of death in patients. Actively controlling symptoms and improving lung function are the mainstays of treatment for this disease. important goal. At present, the main drugs used to relieve the symptoms of COPD patients are long-acting β2 receptor agonists such as formoterol and salmeterol. [0003] Uclidinium bromide, a long-acting cholinergic antagonist (LAMA), and vilanterol, a long-acting adrenoceptor β2-agonist (LABA), both relax bronchial smooth muscle. [0004] AnoroEllipta (umeclidinium bromide / vilanterol) is the second daily anti-COPD compound launched by GSK in 2013, and BreoE...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 付清泉张菊华林强刘正超王建陈志勇
Owner 成都伊诺达博医药科技有限公司
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