Preparation method of mirabegron

A technology of structural formula and compound, which is applied in the field of preparation of mirabegron, can solve the problems of high cost, low yield of synthetic mirabegron, unsuitability for industrial production, etc., and achieves low environmental pollution, convenient yield and purity, The effect of fewer steps

Active Publication Date: 2014-06-18
JIANGXI SYNERGY PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In order to overcome the defects of low yield and high cost of synthesizing mirabegron in the prior art, and being unsuitable for industrialized production, the invention provides a kind of mirabegron with low cost, high yield, few steps, less environmental pollution, and is safe and convenient. The preparation method of Peron, which is suitable for industrialized large-scale production

Method used

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  • Preparation method of mirabegron
  • Preparation method of mirabegron
  • Preparation method of mirabegron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] In a 1000ml reaction flask, put 2-(2-aminothiazole-4-)acetic acid hydrochloride (50g, 0.26mol), triethylamine (39g, 0.39mol), di-tert-butyl dicarbonate (61.6g, 0.28mol), ethanol 500ml, reacted at 20-30°C for 12 hours, recovered the solvent under reduced pressure, added 200ml of water, 100ml of ethyl acetate, extracted and separated layers, washed the organic layer once with 100ml of saturated saline, and concentrated to dryness under reduced pressure to obtain 63g of the compound of structural formula 4, yield 95%.

[0051] In a 2000ml reaction bottle, drop into the compound of the above structural formula 4 (60g, 0.23mol), the compound of the structural formula 3 (54.7g, 0.23mol) substituted by bromine, 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (44.5g, 0.23mol), 1-hydroxybenzotriazole (31.4g, 0.23mol), triethylamine (58.7g, 0.58mol), dichloromethane 700ml, 20-30℃ After 12 hours of reaction, 500ml of water and 100ml of dichloromethane were added, a...

Embodiment 2

[0056] In a 1000ml reaction flask, add 2-(2-aminothiazole-4-)acetic acid hydrochloric acid (50g, 0.26mol), triethylamine (64.9g, 0.64mol), benzyl bromide (44g, 0.28mol), methanol 500ml , reacted at 20-30°C for 10 hours, recovered the solvent under reduced pressure, added 200ml of water, 100ml of ethyl acetate, extracted and separated layers, washed the organic layer once with 100ml of saturated brine, concentrated to dryness under reduced pressure, and obtained 61.6g of the compound of structural formula 4 , yield 93%.

[0057] In a 2000ml reaction bottle, drop into the compound of the above structural formula 4 (60g, 0.24mol), the compound of the structural formula 3 (56.9g, 0.24mol) substituted by bromine, 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (46.3g, 0.24mol), 1-hydroxybenzotriazole (32.7g, 0.24mol), triethylamine (61.1g, 0.60mol), dichloromethane 700ml, 30-40℃ After reacting for 12 hours, add 500ml of water and 100ml of dichloromethane, extract an...

Embodiment 3

[0062] In a 1000ml reaction flask, add 2-(2-aminothiazole-4-)acetic acid hydrochloride (50g, 0.26mol), triethylamine (64.9g, 0.64mol), benyl chloroformate (48.2g, 0.28mol), 500ml of ethyl acetate was reacted at 20-30°C for 10 hours, 200ml of water and 100ml of ethyl acetate were added, the layers were extracted, the organic layer was washed once with 100ml of saturated brine, concentrated under reduced pressure to dryness, and 67.6g of the compound of structural formula 4 was obtained. The yield is 90%.

[0063] In a 2000ml reaction bottle, put the compound of the above structural formula 4 (60g, 0.21mol), the compound of the structural formula 3 (44.2g, 0.23mol) substituted by chlorine, N,N-carbonyldiimidazole (39.9g, 0.25mol), triethyl Amine (31.1g, 0.31mol), ethyl acetate 700ml, react at 40-50°C for 4 hours, add chlorine-substituted compound of structural formula 3 (37.3g, 0.24mol), react at 40-50°C for 8 hours, add water 500ml , 100ml of ethyl acetate was extracted and se...

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Abstract

The invention discloses a preparation method of mirabegron. The preparation method comprises the following steps: I, carrying out a reaction on 2-(2-aminothiazole-4-) acetic hydrochloride shown in a structural formula 5 and an amino protective agent to obtain a compound shown in a structural formula 4; II, carrying out a condensation reaction on the compounds shown in the structural formulae 3 and 4 in the presence of a condensating agent and an acid-binding agent to obtain a compound shown in the structural formula 2; and III, carrying out a substitution reaction on the compound shown in the structural formula 2 and (R)-2-amino-1-phenethyl alcohol under the effect of the acid-binding agent, and after reaction, adding a deprotection group agent to remove the protective group to obtain mirabegron shown in a structural formula 1. The method provided by the invention is few in technological step in the synthetic process, simple, high in yield and free from highly toxic products and suitable for industrialized production on a large scale.

Description

technical field [0001] The invention belongs to the technical field of chemistry and relates to a preparation method of mirabegron. Background technique [0002] Mirabegron, the structural formula is shown in the following formula 1, and the chemical name is: 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino] Ethyl]phenyl]-4-thiazoleacetamide, CAS number: 223673-61-8. [0003] [0004] Mirabegron is a selective β3-adrenoceptor agonist developed by Yamanouchi Pharmaceutical Co., Ltd. (now incorporated into Astellas), which can increase bladder filling and storage by activating the β3-adrenoceptor on the detrusor muscle of the bladder. Urinary capacity, the US Food and Drug Administration (FDA) approved on June 28, 2012 for the treatment of overactive bladder (OAB) with symptoms such as urge urinary incontinence, urgency, and frequent urination. [0005] The preparation method of mirabegron mainly contains following several kinds at present: [0006] Synthetic route o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/40
CPCY02P20/55C07D277/40
Inventor 徐烘材黄伟平蒋元森蒋慧纲刘刚
Owner JIANGXI SYNERGY PHARMA
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