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Recrystallization method of mirabegron alpha crystal form raw material

A mirabegron and recrystallization technology, applied in the field of medicine and chemical industry, can solve the problems of cumbersome operation, difficult to remove, increase material cost, etc., and achieve the effect of easy recovery of solvent, favorable for industrial production, and reduction of production cost.

Pending Publication Date: 2021-12-10
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the disadvantages of these methods are: (1) it is easy to produce mixed crystals of α crystal form and β crystal form; (2) when the mixed solvent is in industrial production, it is difficult to recycle, which increases the cost of materials; (3) adding seed crystals, The operation steps are increased, and the operation is more cumbersome; (4) It takes a long time to cool down and crystallize, which increases the working hours and power costs
[0013] The impurity A is similar to mirabegron in chemical structure and physical and chemical properties, it is difficult to remove, and it is easy to cause the product quality to fail to meet the requirements

Method used

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  • Recrystallization method of mirabegron alpha crystal form raw material
  • Recrystallization method of mirabegron alpha crystal form raw material
  • Recrystallization method of mirabegron alpha crystal form raw material

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0050] Preparation Example: Preparation of Crude Mirabegron

[0051] In a 50L reaction tank, add 15L of purified water, start stirring, and add 1Kg of (R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol hydrochloride (Mira Veron intermediate), 0.67Kg 2-(2-aminothiazol-4-yl) acetic acid hydrochloride and 0.9Kg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Salt (EDCI), after adding, react at room temperature for 5 hours, TLC monitors that the reaction of the Mirabegron intermediate is complete, slowly add 7L of 5% sodium hydroxide aqueous solution that has been prepared in advance, and a white solid is precipitated during the feeding process, and the addition is completed , suction filtration, obtain wet product (purity 98.79%, impurity A content 0.19%, the retention time of impurity A is 39.8min), the purity detection result sees Figure 4 .

[0052] Add 8Kg ethanol and 14Kg water in the reaction tank, add wet product under stirring, be warming up to fully dis...

Embodiment 1-2、 comparative example 1-3

[0053] Embodiment 1-2, comparative example 1-3: the influence of solvent, cooling program and seed crystal on test

[0054] Add solvent into a 1000mL three-neck flask, add 30g of crude product under stirring, heat up and down program and add α-crystal seed (see Table 1 for details), filter with suction, and dry in vacuum at 70°C to obtain the raw material product of Mirabegron.

[0055] Table 1 The effect of cooling program and seed crystal on the test

[0056]

[0057]

[0058] It can be seen from the above table that when using a mixed solvent of water and ethanol for recrystallization, it is necessary to strictly control the heating and cooling program, which takes a long time and needs to add seed crystals at the same time, otherwise the pure target α crystal form raw material cannot be obtained, and When ethanol single solvent is used for recrystallization, the heating and cooling procedure is simple, the time consumption is greatly reduced, and the target α crystal...

Embodiment 2-11

[0059] Example 2-11: Investigation of different types of single solvents and activated carbon

[0060] Add a single solvent in the there-necked flask, add 30g of Mirabegron crude product under stirring, heat up to reflux, after fully dissolving, add activated carbon (see Table 2 for details), filter while hot, and quickly cool down to room temperature in a cold water bath. Suction filtration for about 0.5h, and vacuum drying at 70°C to obtain the raw material of Mirabegron α crystal form.

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Abstract

The invention provides a recrystallization method of a mirabegron alpha crystal form raw material. The method is characterized in that by adopting a single solvent for recrystallization, a target alpha crystal form raw material can be rapidly obtained only by adopting a simple heating and cooling procedure without adding of a seed crystal; by further adding activated carbon for purification, the content of an impurity A can be reduced to 0.1% or below, so that the product quality is greatly improved; and the solvent is easy to recycle, the consumed time is short, the production cost is reduced, the operation is simple, the product purity is high, and industrial production is more facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a method for recrystallization of mirabegron α crystal form raw materials. Background technique [0002] Mirabegron is a drug developed by Japan Astellas Pharmaceutical Co., Ltd. for urgency, frequency and incontinence caused by overactive bladder. It went on the market in Japan in 2011, and was approved by the US FDA on June 28, 2012 for the treatment of overactive bladder (OAB) in adults. [0003] Mirabegron: C 21 h 24 N 4 o 2 S, CAS number: 223673-61-8, Chinese chemical name: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2- Hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide, its structural formula is as follows: [0004] [0005] Prior art WO2003037881A1 (disclosure date 2003.5.8) discloses that there are two crystal forms of Mirabegron raw materials: α-type and β-type, of which α-type crystals are more stable and have good drugg...

Claims

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Application Information

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IPC IPC(8): C07D277/40
CPCC07D277/40C07B2200/13
Inventor 王辉张红芬曹晓冉孙晓伟付香杰何影韩向云杨雪任军乐赵飞船
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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