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Preparation method of umeclidinium bromide

A technology of umeclidinium bromide and raw materials, applied in the field of preparation of umeclidinium bromide, can solve the problems of high price of lithium reagents, harsh use conditions, difficult storage and the like, and achieve the effects of mature equipment, mild reaction conditions and lower refrigeration costs

Inactive Publication Date: 2016-04-06
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lithium reagents are expensive, difficult to store, harsh in use conditions, and relatively high in cost

Method used

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  • Preparation method of umeclidinium bromide
  • Preparation method of umeclidinium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Preparation of phenylmagnesium chloride: under nitrogen protection, add 55g (2.3mol) of metal magnesium tape brightened by sandpaper to 3 liters of tetrahydrofuran, drop 215g (1.91mol) of chlorobenzene, and proceed with slight heating, control the rate of addition to keep the reaction boiling, After about 1.5 hours, the dripping was completed, and after the dripping, the solution was heated under slight reflux for 30 minutes. Let cool and set aside.

Embodiment 2

[0019] Preparation of phenylmagnesium bromide: under the protection of argon, add 50.4g (2.1mol) of metal magnesium tape polished with sandpaper to 4.2 liters of anhydrous ether, drop 300g (1.91mol) of bromobenzene, add a grain of iodine to trigger, and hair dryer The slight heat reaction proceeded, and the addition rate was controlled to keep the reaction boiling, and the dripping was completed in about 1.5 hours, and then heated under slight reflux for 30 minutes after the dripping was completed. Let cool and set aside.

Embodiment 3

[0021] Preparation of crude product: ethyl azabicyclo[2.2.2]octane-4-carboxylate (135g, 0.736mol) was dissolved in 3L tetrahydrofuran, under the protection of nitrogen, the solution was cooled to -5~0°C, and 300g of brominated Grignard reagent prepared from benzene. After stirring at -5~0°C for 1 hour (sampling TLC to monitor the progress of the reaction). Add 50ml of water to quench. The liquids were separated, and the aqueous phase was extracted twice with 500 ml of tetrahydrofuran, the combined organic phases were washed with water, dried and filtered. Part of the solvent was removed under reduced pressure, and the remainder was kept at about 1 L. The residue was stirred at 20°C overnight for crystallization. Filter, wash (petroleum ether 2×200ml), and vacuum-dry the filter cake at 40°C to obtain 121.2g of yellow-white crystals, with a yield of 54.2%.

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Abstract

The invention discloses a preparation method of umeclidinium bromide. The method is suitable for industrial routine reactions, and industrial production schemes exist at present. A technical scheme adopted in the invention is characterized in that a Grignard reagent is adopted to substitute a lithium reagent, bromobenzene, chlorobenzene and other benzene halides are adopted as raw materials, and ether and tetrahydrofuran can be used as a solvent. Compared with the prior art, the method disclosed in the invention has the following advantages: 1, the lithium reagent with high price is substituted by magneson; 2, reaction conditions are mild, too low temperature is not needed, and the reaction temperature is about 0-5DEG C, so the refrigeration cost is reduced; and 3, a routine device can be used, and the Grignard reaction is a classic reaction and industrially exists for a hundred years or above, so people can be simply trained, and the device is mature and has high operating stability.

Description

technical field [0001] The invention relates to a preparation method, in particular to a preparation method of umeclidinium bromide. Background technique [0002] The preparation patents of umeclidinium bromide US7439393, USRE44874, US7488827, US7498440, US7361787, etc. use phenyllithium reaction to prepare intermediate 4-[(diphenyl)hydroxymethyl]azabicyclo[2.2.2]octane. The specific method is as follows: ethyl azabicyclo[2.2.2]octane-4-carboxylate undergoes nucleophilic addition reaction with 2.02-2.5 times the amount of phenyllithium, and the reaction temperature is controlled at -78°C~-15°C. Lithium reagents are expensive, difficult to store, harsh in use conditions, and relatively high in cost. Contents of the invention [0003] In order to overcome the above-mentioned deficiencies in the prior art, the present invention improves the type of reaction, changing the original reaction into a conventional reaction suitable for industrialization, and this type of reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 李学坤许坤
Owner ANHUI DEXINJIA BIOPHARM
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