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Recrystallization method and preparation method of mirabegron

A recrystallization and crystallization technology, which is applied in the recrystallization method and preparation field of Mirabegron, can solve the problems of cumbersome process steps and high cost of raw materials, and achieve the effects of simple operation process, low production cost and content reduction

Active Publication Date: 2022-03-22
BEIJING ZHENDONG GUANGMING PHARMA RES INST
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in order to avoid the formation of impurity imA, the new process steps are relatively cumbersome and the cost of raw materials is high

Method used

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  • Recrystallization method and preparation method of mirabegron
  • Recrystallization method and preparation method of mirabegron
  • Recrystallization method and preparation method of mirabegron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-4

[0071] Add 400mL of water and 6.15g of concentrated hydrochloric acid into a 1L three-necked flask, stir well, then add 100g of (R)-2-(4-aminophenethylamino)-1-phenylethanol dihydrochloride, 48g 2-aminothiazole-4-acetic acid, 70 g of EDCI, stirred at room temperature for 1 h. HPLC monitoring, the reaction is complete. Transfer to a 2L beaker, add 400mL of water, stir evenly, slowly add NaOH solution with a mass fraction of 20% dropwise, a white solid precipitates out, adjust the pH to 9-10, stir for 30min, and filter. The filter cake was beaten with 2L of 15% ethanol aqueous solution, suction filtered, and air-dried at 45-50°C to obtain 114.2 g of Mirabegron crude product, with a yield of 94.8%, a purity of 99.62%, and an imA content of 0.21%. The liquid phase analysis chromatogram of mirabegron crude product is as follows figure 1 as shown, figure 2 for figure 1 A zoomed-in view of the LC analysis spectrum.

[0072] Embodiment provides the recrystallization method of mi...

Embodiment 5-8

[0079] Embodiment provides the recrystallization method of mirabegron, comprises the steps:

[0080] Add the mixed solvent into the three-neck flask, heat the mixed solvent to reflux temperature, add the crude Mirabegron under the condition of 150rpm mechanical stirring, stir and dissolve, a white solid precipitates out, naturally cool down to room temperature and stir for 3 hours, then filter and collect the solid , The solid was air-dried at room temperature to obtain pure Mirabegron.

[0081] Wherein, in the recrystallization process of different embodiments, the type and dosage of the crude product used, the composition and dosage of the mixed solvent, the amount of pure Mirabegron obtained, the yield of pure Mirabegron, the purity of pure Mirabegron, See Table 3-4 for the content information of imA impurity in pure Mirabegron.

[0082] The operating conditions of different embodiments of table 3

[0083]

[0084] The pure product result of Mirabegron obtained by the ...

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Abstract

The invention relates to the technical field of purification of chemical drugs, in particular to a recrystallization method and preparation method of Mirabegron. The recrystallization method of mirabegron comprises the following steps: after the crude product of mirabegron is dissolved in a mixed solvent under the condition of reflux temperature, the temperature is lowered to crystallize, and the solid is collected; the mixed solvent includes alcohol solvent and dichloromethane. In the recrystallization method of the present invention, through the regulation of the mixed solvent, the Mirabegron of the β crystal form will quickly transform into the α crystal form after being dissolved in the specific mixed solvent, and the solubility in the specific mixed solvent system will decrease after crystallization , and slowly precipitate out, so that other impurity components can be separated from Mirabegron to achieve the purpose of purification; especially for the imA impurity in the crude Mirabegron, reduce the content of impurity imA in the product, and the crude product obtained on the basis of the original process route The simple crystallization and purification carried out, the operation process is simple, and the production cost is low, which is of great significance to the research and development and application of mirabegron medicine.

Description

technical field [0001] The invention relates to the technical field of purification of chemical drugs, in particular to a recrystallization method and preparation method of Mirabegron. Background technique [0002] Mirabegron is a drug used to treat urgency, frequency and incontinence caused by overactive bladder. It was first launched in Japan in 2011. On June 28, 2012, it was approved by the US Food and Drug Administration (FDA) for the treatment of overactive bladder (OAB) in adults. Mirabegron: C 21 h 24 N 4 o 2 S, the Chinese chemical name is: (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid acyl Aniline, its structure is shown in formula (Ⅲ): [0003] [0004] There are two main synthetic routes of Mirabegron: [0005] Synthetic route 1: (R)-styrene oxide and 4-nitrophenethylamine are used as starting materials, after dehydration condensation, palladium carbon hydrogenation to reduce the nitro group, and then dehydration con...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/40B01D9/02
CPCC07D277/40B01D9/005C07B2200/13C07B2200/07B01D2009/0086
Inventor 何海晓张永林雷飞熊继业王新锋马士锋
Owner BEIJING ZHENDONG GUANGMING PHARMA RES INST
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