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Synthesis method of mirabegron

A synthesis method and compound technology, applied in the field of synthesis, can solve problems such as not suitable for large-scale industrial production, high impurity content, complicated operation, etc., and achieve the effect of avoiding the use of high boiling point solvents, reducing impurity content, and reducing solvent consumption

Inactive Publication Date: 2014-12-24
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The technical problem to be solved by the present invention is to provide an improved Mirabegron in order to overcome the defects of complex operation, high cost, high impurity content and unsuitability for large-scale industrial production in the existing method for preparing Mirabegron. Veron's Synthesis Method

Method used

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  • Synthesis method of mirabegron
  • Synthesis method of mirabegron
  • Synthesis method of mirabegron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1, a kind of synthetic method of mirabegron

[0029] Including the following steps:

[0030] step 1)

[0031] Into a 50L glass reactor, add 1.01kg of R-mandelic acid, 1.4kg of 4-nitrophenethylamine hydrochloride, 0.1kg of HOBt, 6L of DMF; slowly add 0.7kg of triethylamine dropwise while controlling the internal temperature to ≤25°C; After the dropwise addition is completed, add EDC in batches. After the addition is complete, continue to stir for 1-2 hours; TLC monitors the completion of the reaction, add 14L ethyl acetate and 28L water, stir for 30 minutes, let stand to separate, and use 1mol / L hydrochloric acid solution for the organic phase 15L was washed once, and 20% (w / w) potassium carbonate aqueous solution was washed twice (15L each time); the organic phase was dried, suction filtered, and concentrated to obtain the crude product; the crude product was recrystallized with toluene to obtain a white solid (intermediate compound I) 1.90kg , yield 9...

Embodiment 2

[0038] Embodiment 2, a kind of synthetic method of mirabegron

[0039] Including the following steps:

[0040] step 1)

[0041] Into a 50L glass reactor, add 1.01kg of R-mandelic acid, 1.4kg of 4-nitrophenethylamine hydrochloride, 0.1kg of HOBt, 6L of DMF; slowly add 0.7kg of triethylamine dropwise while controlling the internal temperature to ≤25°C; After the dropwise addition is completed, add EDC in batches. After the addition, continue to stir for 1-2 hours; TLC monitors the completion of the reaction; add 14L ethyl acetate and 28L water, stir for 30 minutes, let stand to separate, and use 1mol / L hydrochloric acid solution for the organic phase 15L was washed once, and 20% (w / w) potassium carbonate aqueous solution was washed twice (each time 15L); the organic phase was dried, suction filtered, and concentrated to obtain the crude product; the crude product was recrystallized with toluene to obtain a white solid (intermediate compound I) 1.95kg , yield 93%, content...

Embodiment 3

[0048] Embodiment 3, a kind of synthetic method of mirabegron

[0049] Including the following steps:

[0050] step 1)

[0051] Add 1.01kg of R-mandelic acid, 1.4kg of 4-nitrophenethylamine hydrochloride, 0.2kg of HOBt, and 6L of DMF into a 50L glass reactor; slowly add 0.7kg of triethylamine dropwise while controlling the internal temperature to ≤25°C; After the dropwise addition is completed, add EDC in batches. After the addition, continue to stir for 1-2 hours; TLC monitors the completion of the reaction; add 14L ethyl acetate and 28L water, stir for 30 minutes, let stand to separate, and use 1mol / L hydrochloric acid solution for the organic phase 15L was washed once, and 20% (w / w) potassium carbonate aqueous solution was washed twice (15L each time); the organic phase was dried, suction filtered, and concentrated to obtain the crude product; the crude product was recrystallized with toluene to obtain a white solid (intermediate compound I) 1.92kg , yield 91%, cont...

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Abstract

The invention provides a synthesis method of mirabegron. The synthesis method comprises the following steps: (1) in a tetrahydrofuran solvent and a nitrogen atmosphere, reducing a compound I into a compound II by adopting a reducing agent; (2) in an alcohol solvent and a hydrogen environment, reducing the compound II into a compound III by adopting palladium-on-carbon catalytic hydrogenation; and (3) in a water solvent and under an acidic condition, mixing the compound III with 2-amino-4-thiazole acetic acid, and performing condensation reaction under the action of a condensing agent, to obtain mirabegron. The method has the advantages of being mild in reaction conditions, high in yield and low in cost, and the provided mirabegron is low in the content of impurities, therefore, the synthesis method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a synthesis method of aryl ethanolamine compounds, in particular to a synthesis method of mirabegron. Background technique [0002] The Chinese chemical name of Mirabegron: (R) -2-(2-Amino-1,3-thiazol-4-yl)-4'-[2-[(2-Hydroxy-2-phenylethyl Base)amino]ethyl]phenylacetamide; English chemical name: (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl ]acetanilide; Molecular formula: C 21 h 24 N 4 o 2 S; molecular weight: 396; CAS registration number: 223673-61-8, the chemical structure of mirabegron is shown below. [0003] [0004] Mirabegron belongs to the class of aryl ethanolamine β3 receptor agonists, acting on the bladder detrusor smooth muscle β 3 Adrenaline receptors make the bladder dilate, promote bladder filling and increase urine storage capacity, can effectively reduce the frequency of urination, and improve urinary frequency, urgency and urinary incontinence caused by overactive bladder. T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/40
CPCC07D277/40
Inventor 葛德培吴其华
Owner 安徽联创生物医药股份有限公司
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