Crystal transformation solvent, application thereof and preparation method of mirabegron alpha crystal form

A mirabegron and solvent technology, applied in organic chemistry methods, organic chemistry, etc., can solve problems such as the α crystal form, and achieve low cost, low energy consumption, and the effect of ensuring product quality and safety

Pending Publication Date: 2022-05-27
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, all the examples described in CN 1575287A show that in the mixed solvent of ethanol and water without adding crystal seeds or adding β crystal forms as seeds, the products obtained are all β crystal forms, and only when α crystals are added In the case of crystal seed crystals, the α crystal form with better stability can be obtained. In this case, there will be a problem: in the absence of Mirabegron α crystal form or the inability to obtain Mirabegron α crystal form as a seed crystal , there is no way to prepare α crystal form with better stability through this method; that is to say, the necessary prerequisite for this method to be implemented is that α crystal form can be used as a seed crystal in advance, otherwise it will be impossible to implement, so this method Significant limitations exist in implementation and application

Method used

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  • Crystal transformation solvent, application thereof and preparation method of mirabegron alpha crystal form
  • Crystal transformation solvent, application thereof and preparation method of mirabegron alpha crystal form
  • Crystal transformation solvent, application thereof and preparation method of mirabegron alpha crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] 1. Preparation of compound 3

[0114]

[0115] Include the following steps:

[0116] ①, in 240kg N,N-dimethylformamide, add 26.02kg (about 171mol) D-mandelic acid (compound 1), 31.5kg (about 155.45mol) 4-nitrophenethylamine hydrochloride (compound 2), 23.12kg (about 171mol) 1-hydroxybenzotriazole, and 35.28kg (about 171mol) N, N-dicyclohexylcarbodiimide, 18.84kg (about 186mol) triethylamine, the temperature of reaction is at 20~25 ℃, stirring and reacting for 5h, after high performance liquid chromatography (HPLC) detects that the reaction is basically complete (the remaining amount of compound 2 is less than or equal to 2%), a reaction solution is obtained;

[0117] 2., in above-mentioned reaction solution, add 360kg ethyl acetate and 604.8kg purified water, stir, pad diatomaceous earth filter afterwards, stand, separatory, get organic phase, the water phase of lower floor is with ethyl acetate (285kg, 171kg) Extract twice, combine the organic phases, add 32.82kg ...

Embodiment 2～4

[0151] In step i of the preparation method of compound 4, the amount of 1,3-dimethylimidazolidinone (DMI) was changed to 0mol, 200mol, and 600mol respectively, that is: in terms of compound 3 (mol), 1,3-dimethylimidazolidinone (DMI) The consumption of diimidazolidinone (DMI) is respectively 0 equivalent, 2.5 equivalent, 7.5 equivalent, other process conditions remain unchanged (identical to embodiment 1), prepare compound 4, and its yield and HPLC purity, impurity content are shown in Table 3 .

[0152]

[0153] Table 3, the effect of 1,3-dimethylimidazolidinone (DMI) dosage on the preparation of compound 4

[0154] Example 2 Example 3 Example 1 Example 4 DMI dosage / equivalent 0 2.5 5 7.5 yield 83.0％ 86.6％ 88.7％ 89.2％ HPLC purity 96.7％ 99.61％ 99.6％ 99.44％ Impurities (337008) 3.1％ ND ND ND

[0155] ND means not detected, which means its content is below the detection limit.

Embodiment 5～6

[0157] In step i of the preparation method of compound 4, the dosage of borane dimethyl sulfide was changed to 168 mol and 200 mol, respectively, that is, in terms of compound 3 (mol), the dosage of borane dimethyl sulfide was respectively 2.1 equivalent and 2.5 equivalent. , other process conditions remain unchanged (same as Example 1), compound 4 is prepared, and its yield, HPLC purity and impurity content are shown in Table 4.

[0158] Table 4, the effect of borane dimethyl sulfide dosage on the preparation of compound 4

[0159] Example 5 Example 1 Example 6 Borane dimethyl sulfide amount / equivalent 2.1 2.3 2.5 yield 86.0％ 88.7％ 88.5％ HPLC purity 99.76％ 99.6％ 99.73％ Impurities (337008) ND ND ND

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PUM

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Abstract

The invention provides a crystal transformation solvent and application thereof and a preparation method of a mirabegron alpha crystal form. According to the present invention, by using the newly found property of the solvent combination of the isopropyl acetate solvent and the water, the conversion from the mirabegron beta crystal form to the mirabegron alpha crystal form is successfully achieved by using the solvent combination as the mirabegron crystal transformation solvent, such that the mirabegron alpha crystal form can be prepared without the seed crystal, the process conditions are mild, the cost is low, and the method is suitable for industrial production. The method is convenient to operate and control, high in yield and purity, low in energy consumption, low in cost, safe, environment-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical crystal forms, and in particular relates to a crystallizing solvent and application thereof and a preparation method of mirabegron alpha crystal form. Background technique [0002] Overactive Bladder (OAB) is a syndrome characterized by urinary urgency, often accompanied by frequent urination, urinary incontinence, etc. . [0003] Mirabegron, CAS No.: 223673-61-8, with the following structural formula, is a selective β3-adrenergic receptor agonist, mainly used for the treatment of urinary urgency, frequency and incontinence caused by overactive bladder Equivalent. It was first listed in Japan in 2011, and later in the United States, the European Union and other countries or regions. It has been widely praised by patients due to its advantages of good therapeutic effect and small side effects. [0004] [0005] At present, a mainstream route for synthesizing mirabegron is: taking 4-nitrophenethy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/40
CPCC07D277/40C07B2200/13
Inventor 魏彦君孔猛刘希望徐青景邢艳平
Owner SHANGHAI VIWIT PHARMA CO LTD
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