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Recrystallization method of mirabegron and preparation method thereof

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

Active Publication Date: 2020-04-28
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 of mirabegron and preparation method thereof
  • Recrystallization method of mirabegron and preparation method thereof
  • Recrystallization method of mirabegron and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-4

[0071] Add 400mL of water and 6.15g of concentrated hydrochloric acid to a 1L three-necked flask. After stirring, add 100g of (R)-2-(4-aminophenethylamino)-1-phenylethanol dihydrochloride, 48g The 2-aminothiazole-4-acetic acid and 70g EDCI were stirred at room temperature for 1h. HPLC monitoring, the reaction is complete. Transfer to a 2L beaker, add 400 mL of water, and slowly add 20% NaOH solution dropwise after stirring. A white solid precipitates. Adjust the pH to 9-10. After stirring for 30 minutes, filter. The filter cake was slurried with 2L of ethanol aqueous solution with a volume fraction of 15%, filtered with suction, and dried at 45-50° C. to obtain 114.2 g of crude Mirabegron with a yield of 94.8%, purity: 99.62%, and imA content: 0.21%. The liquid phase analysis spectrum of the crude Mirabegron is as follows figure 1 As shown, figure 2 for figure 1 An enlarged view of the liquid phase analysis spectrum.

[0072] The embodiment provides a recrystallization method ...

Embodiment 5-8

[0079] The embodiment provides a recrystallization method of Mirabegron, which includes the following steps:

[0080] Add the mixed solvent to the three-necked flask, heat the mixed solvent to the reflux temperature, add the crude Mirabegron under mechanical stirring at 150rpm, stir to dissolve, white solid precipitates, naturally cool to room temperature and stir for 3h, then filter, collect the solid , Dry the solid at room temperature by blowing air to obtain pure Mirabegron.

[0081] Among them, in the recrystallization process of different embodiments, the crude species and amount used, the composition and amount of the mixed solvent, the amount of pure Mirabegron obtained, the yield of pure Mirabegron, the purity of pure Mirabegron, The content of imA impurity in Mirabegron pure product is shown in Table 3-4.

[0082] Table 3 Operating conditions of different embodiments

[0083]

[0084] Table 4 Results of pure Mirabegron obtained by recrystallization in different examples

[0...

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Abstract

The invention relates to the technical field of purification of chemical drugs, in particular to a recrystallization method of mirabegron and a preparation method thereof. The recrystallization methodof mirabegron comprises the following steps: dissolving a mirabegron crude product in a mixed solvent under a reflux temperature condition, cooling for crystallization, and collecting a solid; wherein the mixed solvent comprises an alcohol solvent and dichloromethane. According to the recrystallization method disclosed by the invention, by regulating and controlling the mixed solvent, the mirabegron in the beta crystal form can be rapidly converted into the alpha crystal form after being dissolved in the specific mixed solvent, the solubility of the mirabegron in the specific mixed solvent system is reduced after crystal transformation, and the mirabegron is slowly separated out, so that other impurity components are separated from the mirabegron, and the purification purpose is achieved;the method has the advantages of simple operation process, low production cost, reduction of the impurity imA content in the product especially for the imA impurity in the mirabegron crude product, simple crystallization and purification of the crude product obtained on the basis of the original process route, and important meaning for the research, development and application of mirabegron medicines.

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 urinary urgency, frequent urination and urinary incontinence caused by overactive bladder. It was first marketed in Japan in 2011. On June 28, 2012, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of overactive bladder (OAB) in adults. Mirabellon: 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 for Mirabegron: [0005] Synthetic route 1: (R)-styrene oxide and 4-nitrophenethylamine as starting materials, after dehydration condensation, palladium hydrogenation to reduce the nitro group, and then dehydration condens...

Claims

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Application Information

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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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