223673-61-8

Basic information

• Product Name: Mirabegron
• Synonyms: 4-Thiazoleacetamide, 2-amino-N-(4-(2-(((2R)-2-hydroxy-2-phenylethyl)amino)ethyl)phenyl)-;Mirabegron;N-(4-(2-(2-hydroxy-2-phenylethylamino)ethyl)phenyl)-2-(2-aminothiazol-4-yl)acetamide;2-AMino-N-[4-[2-[[(2R)-2-hydroxy-2-phenyl-ethyl]aMino]-ethyl]phenyl]-4-thiazoleacetaMide;2-(2-aMino-1,3-thiazol-4-yl)-N-(4-{2-[(2-hydroxy-2-phenylethyl)aMino]ethyl}phenyl)acetaMide;(2R)-2-(2-AMinothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)aMino]ethyl]acetic Acid Anilide;YM 178;Mirabegron(YM 178)
• CAS NO: 223673-61-8
• Molecular Formula: C₂₁H₂₄N₄O₂S
• Molecular Weight: 396.506
• EINECS: 1592732-453-0
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 223673-61-8.mol

Chemical Properties

• Melting Point: 138-140°C
• Boiling Point: 690.008 °C at 760 mmHg
• Flash Point: 371.104 °C
• Appearance: /
• Density: 1.313
• Vapor Pressure: 5.45E-20mmHg at 25°C
• Refractive Index: 1.68
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly, Heated), Methanol (Slightly)
• PKA: 13.51±0.70(Predicted)
• CAS DataBase Reference: Mirabegron(CAS DataBase Reference)
• NIST Chemistry Reference: Mirabegron(223673-61-8)
• EPA Substance Registry System: Mirabegron(223673-61-8)

Safety Data

• Hazardous Substances Data: 223673-61-8(Hazardous Substances Data)

Usage

Uses

Mirabegron is used as a potent bladder relaxant compound for the treatment of overactive bladder syndrome. It increases bladder capacity without influencing the frequency of bladder contraction, providing relief from urgency, urinary frequency, and urinary urge urinary incontinence.
Used in Pharmaceutical Industry:
Mirabegron is used as an internal standard for the quantification of Mirabegron by GCor LC-mass spectrometry, aiding in the accurate measurement and analysis of the compound in various applications.
Used in Overactive Bladder Treatment:
Mirabegron is used as a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), helping to manage symptoms such as urgency, urinary frequency, and urinary urge urinary incontinence.

Originator

Astellas Pharma Inc. (Japan)

Clinical Use

Mirabegron is an orally active β3-adrenoceptor agonist currently in development by Astellas Pharma for the treatment of overactive bladder (OAB). The drug is a nanomolar EC50 antagonist against human β3-AR biochemical assays with good selectivity over b1- and β2-ARs. Mirabegron demonstrates a novel mechanism by targeting the β3-AR for bladder relaxation to help manage OAB symptoms such as increased urinary urgency and frequency and urgency incontinence. However, mirabegron is a cytochrome P450 2D6 inhibitor, and it raises a concern for drug–drug interaction with concomitant administration of other cytochrome P450 2D6 substrates.

Synthesis

The synthesis of mirabegron began with a condensation reaction between (R)-styrene oxide (182) and 4-nitrophenylethylamine (183) in refluxing isopropanol to yield corresponding aminoalcohol 184 in 22% yield. Aminoalcohol 184 was protected as its N-Boc derivative with t-butyl dicarbonate in THF in 96% yield, and this was followed by nitro group hydrogenative reduction with 10% Pd/C to give free amine 185 in 96% yield. Aniline 185 was coupled with 2-amino-4-thiazolyl acetic acid 186 in the presence of EDCI and HOBt to give amide 187 in 85% yield. Removal of the Boc group was affected with 4 N HCl solution in a 2:1 volume ratio in ethyl acetate to obtain mirabegron HCl in 52% yield. The HCl salt was neutralized with 1 N NaOH to deliver mirabegron (XVII).

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

Metabolised via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration.

InChI:InChI=1/C21H24N4O2S/c22-21-25-18(14-28-21)12-20(27)24-17-8-6-15(7-9-17)10-11-23-13-19(26)16-4-2-1-3-5-16/h1-9,14,19,23,26H,10-13H2,(H2,22,25)(H,24,27)

Synthetic route

2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide acetate salt → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With water In water at 80℃; for 24h; Reagent/catalyst; Temperature;	100%

2-amino-4-thiazoleacetic acid (29676-71-9) + YM-208876 (391901-45-4) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Stage #1: 2-amino-4-thiazoleacetic acid; YM-208876 In water at 20℃; for 0.0833333h; Stage #2: With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 20℃; for 1h; Reagent/catalyst; Temperature;	92.6%
With hydrogenchloride; 1,2-dichloro-ethane In water at 30℃; for 5h;	88.31%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In d7-N,N-dimethylformamide at 25℃; for 13h; Reagent/catalyst;	84%
With hydrogenchloride; dmap In water at 20℃; for 6h;	79%
Stage #1: 2-amino-4-thiazoleacetic acid; YM-208876 With hydrogenchloride In water at 25 - 30℃; for 0.25h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 25 - 30℃; Stage #3: With sodium hydroxide In water at 0 - 5℃; pH=9;	144 g

2-amino-4-thiazoleacetic acid (29676-71-9) + (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethan-1-ol hydrochloride → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 15 - 20℃; for 1h; pH=1.8 - 2;	92%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 20 - 25℃; for 4h; Concentration;	82%
With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water for 1h;

C26H32N4O4S → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; water at 20℃; for 10h;	90.3%

2-amino-4-thiazoleacetic acid (29676-71-9) + (R)-2-[ [2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride (521284-22-0) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 28℃; for 3h; Concentration;	84.5%
Stage #1: 2-amino-4-thiazoleacetic acid; (R)-2-[ [2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride With hydrogenchloride In water at 25 - 30℃; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 25 - 30℃; for 2h;	84%
Stage #1: 2-amino-4-thiazoleacetic acid; (R)-2-[ [2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 15 - 20℃; for 1h; Stage #2: With sodium hydroxide In water

(R)-2-(2-(1,3-dioxoindolin-2-yl)thiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)ethyl)phenyl)acetamide → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With hydrazine hydrate In ethanol for 3h; Reflux;	84%
With hydrazine hydrate In ethanol for 3h; Reflux;	84%

2-amino-4-thiazoleacetic acid (29676-71-9) + (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide hydrochloride → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 20℃; for 1h;	75.7%

(2-amino-1,3-thiazol-4-yl)acetyl chloride + YM-208876 (391901-45-4) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With potassium carbonate In acetone at 10 - 15℃;	70%

C22H24N4O3S → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With sodium hydroxide at 55 - 60℃; for 3h;	70%

(R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide monotartrate → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With sodium hydroxide In 2-methyltetrahydrofuran; water pH=9;	63%

(R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide hydrobromide → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With sodium hydroxide In 2-methyltetrahydrofuran; water pH=9;	63%

(R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide oxalate → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With sodium hydroxide In 2-methyltetrahydrofuran; water pH=9;	52%

2-(2-aminothiazol-4-yl)acetic acid hydrochloride + YM-208876 (391901-45-4) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Stage #1: 2-(2-aminothiazol-4-yl)acetic acid hydrochloride; YM-208876 With hydrogenchloride In water at 25 - 30℃; for 0.25h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 25 - 30℃; Stage #3: With sodium hydroxide In water at 0 - 5℃; pH=9;	43 g

(R)-2-(2-aminothiazole-4-yl)-4’-[2-[(2-hydroxy-2-phenyl)ethylamino]ethyl]acetanilide monohydrochloride → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With sodium hydroxide In water at 25 - 30℃;	43 mg

4-tert-butoxycarbonylaminophenylacetonitrile (1233249-35-8) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: hydrogen; ammonia / water; methanol / 4 h / 25 - 30 °C / 2585.81 - 3102.97 Torr 2.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / 2-methyltetrahydrofuran / 2 h / 25 - 30 °C 3.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C 4.1: sodium hydroxide / water / 10 - 15 °C / pH 9 - 10 4.2: 4 h / 5 - 65 °C / Inert atmosphere 4.3: 0.5 h / 5 - 10 °C 5.1: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 15 - 20 °C / pH 1.8 - 2 View Scheme

4-(2-aminoethyl)-N-(tert-butoxycarbonyl)phenylamine (457631-44-6) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / 2-methyltetrahydrofuran / 2 h / 25 - 30 °C 2.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C 3.1: sodium hydroxide / water / 10 - 15 °C / pH 9 - 10 3.2: 4 h / 5 - 65 °C / Inert atmosphere 3.3: 0.5 h / 5 - 10 °C 4.1: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 15 - 20 °C / pH 1.8 - 2 View Scheme

(R)-N-(4-N-Boc-aminophenethyl)-2-hydroxy-2-phenylacetamide → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C 2.1: sodium hydroxide / water / 10 - 15 °C / pH 9 - 10 2.2: 4 h / 5 - 65 °C / Inert atmosphere 2.3: 0.5 h / 5 - 10 °C 3.1: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 15 - 20 °C / pH 1.8 - 2 View Scheme

4-Nitrophenylacetonitrile (555-21-5) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: hydrogen; palladium 10% on activated carbon / ethyl acetate / 20 - 25 °C / 2585.81 - 3102.97 Torr 2.1: ethyl acetate / 25 - 30 °C 3.1: hydrogen; ammonia / water; methanol / 4 h / 25 - 30 °C / 2585.81 - 3102.97 Torr 4.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / 2-methyltetrahydrofuran / 2 h / 25 - 30 °C 5.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C 6.1: sodium hydroxide / water / 10 - 15 °C / pH 9 - 10 6.2: 4 h / 5 - 65 °C / Inert atmosphere 6.3: 0.5 h / 5 - 10 °C 7.1: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 15 - 20 °C / pH 1.8 - 2 View Scheme
Multi-step reaction with 4 steps 1: hydrazine; palladium 10% on activated carbon / ethanol / 2 h / 25 °C / Inert atmosphere 2: hydrazine / 5 h / 25 - 60 °C / Inert atmosphere 3: acetonitrile / 10 h / 70 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / d7-N,N-dimethylformamide / 13 h / 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: diisobutylaluminium hydride / toluene / 2 h / 0 - 10 °C / Inert atmosphere 2.1: triethylamine / methanol / 2 h / 20 °C / Inert atmosphere 2.2: 1 h / 0 °C / Inert atmosphere 3.1: ammonium formate; palladium on activated charcoal / methanol / 6 h / 50 °C 4.1: hydrogenchloride; dmap / water / 6 h / 20 °C View Scheme

phenylacetonitrile (140-29-4) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: nitric acid; phosphoric acid / water / 2 h / 0 - 25 °C 2.1: hydrogen; palladium 10% on activated carbon / ethyl acetate / 20 - 25 °C / 2585.81 - 3102.97 Torr 3.1: ethyl acetate / 25 - 30 °C 4.1: hydrogen; ammonia / water; methanol / 4 h / 25 - 30 °C / 2585.81 - 3102.97 Torr 5.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / 2-methyltetrahydrofuran / 2 h / 25 - 30 °C 6.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C 7.1: sodium hydroxide / water / 10 - 15 °C / pH 9 - 10 7.2: 4 h / 5 - 65 °C / Inert atmosphere 7.3: 0.5 h / 5 - 10 °C 8.1: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 15 - 20 °C / pH 1.8 - 2 View Scheme

p-aminophenylacetonitrile (3544-25-0) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: ethyl acetate / 25 - 30 °C 2.1: hydrogen; ammonia / water; methanol / 4 h / 25 - 30 °C / 2585.81 - 3102.97 Torr 3.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / 2-methyltetrahydrofuran / 2 h / 25 - 30 °C 4.1: hydrogenchloride / water; ethyl acetate / 4 h / 20 °C 5.1: sodium hydroxide / water / 10 - 15 °C / pH 9 - 10 5.2: 4 h / 5 - 65 °C / Inert atmosphere 5.3: 0.5 h / 5 - 10 °C 6.1: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 15 - 20 °C / pH 1.8 - 2 View Scheme
Multi-step reaction with 3 steps 1: hydrazine / 5 h / 25 - 60 °C / Inert atmosphere 2: acetonitrile / 10 h / 70 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / d7-N,N-dimethylformamide / 13 h / 25 °C View Scheme

[2-(formylamino)-1,3-thiazol-4-yl]acetyl chloride (782441-52-5) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 10 - 15 °C 2: sodium hydroxide / 3 h / 55 - 60 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / dichloromethane / 10 - 15 °C 2: potassium carbonate / dichloromethane / 1 h / 25 - 30 °C 3: sodium hydroxide / 3 h / 55 - 60 °C View Scheme

[2-(formylamino)-1,3-thiazol-4-yl]acetic acid → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus pentachloride / dichloromethane / -10 °C 2: potassium carbonate / acetonitrile / 10 - 15 °C 3: sodium hydroxide / 3 h / 55 - 60 °C View Scheme
Multi-step reaction with 4 steps 1: phosphorus pentachloride / dichloromethane / -10 °C 2: potassium carbonate / dichloromethane / 10 - 15 °C 3: potassium carbonate / dichloromethane / 1 h / 25 - 30 °C 4: sodium hydroxide / 3 h / 55 - 60 °C View Scheme

[2-(formylamino)-1,3-thiazol-4-yl]acetic acid + YM-208876 (391901-45-4) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; hydrogenchloride / water / 0.5 h / 25 - 30 °C 2: sodium hydroxide / 3 h / 55 - 60 °C View Scheme

(2-amino-1,3-thiazol-4-yl)acetyl chloride → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 10 - 15 °C 2: potassium carbonate / dichloromethane / 1 h / 25 - 30 °C View Scheme

2-amino-4-thiazoleacetic acid (29676-71-9) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 5 °C 2: potassium carbonate / acetone / 10 - 15 °C View Scheme
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 5 °C 2: potassium carbonate / dichloromethane / 10 - 15 °C 3: potassium carbonate / dichloromethane / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 3 h / 20 - 25 °C 1.2: 1 h / 20 - 25 °C 2.1: sodium hydroxide / water; 2-methyltetrahydrofuran / pH 9 View Scheme

4-nitrophenyl-[2-(formylamino)-1,3-thiazol-4-yl]acetate → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 1 h / 25 - 30 °C 2: sodium hydroxide / 3 h / 55 - 60 °C View Scheme

4-nitrophenyl-(2-amino-1,3-thiazol-4-yl)acetate + YM-208876 (391901-45-4) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
With potassium carbonate In dichloromethane at 25 - 30℃; for 1h;	1 g

(R)-Mandelic Acid (611-71-2) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 6 h / 30 °C 2: 1,3-dimethyl-2-imidazolidinone; borane-THF / tetrahydrofuran / 4 h / 70 °C 3: ammonium formate; palladium 10% on activated carbon / methanol / 5 h / 65 °C / Reflux 4: hydrogenchloride; 1,2-dichloro-ethane / water / 5 h / 30 °C View Scheme

(2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide (521284-19-5) → (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,3-dimethyl-2-imidazolidinone; borane-THF / tetrahydrofuran / 4 h / 70 °C 2: ammonium formate; palladium 10% on activated carbon / methanol / 5 h / 65 °C / Reflux 3: hydrogenchloride; 1,2-dichloro-ethane / water / 5 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogen; palladium 10% on activated carbon / methanol / 4 h / 20 - 25 °C 2: aluminum (III) chloride; lithium aluminium tetrahydride / tetrahydrofuran / 5 h / Reflux 3: hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / water / 1 h / 20 °C View Scheme

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) → (R)-2-(2-aminothiazole-4-yl)-4’-[2-[(2-hydroxy-2-phenyl)ethylamino]ethyl]acetanilide monohydrochloride

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 75℃; for 0.25h;	99%
With hydrogenchloride In methanol; isopropyl alcohol at 20 - 25℃; for 3h;	70 g

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + citric acid (77-92-9) → mirabegron citrate

Conditions	Yield
In methanol at 20℃; for 2h;	94.6%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + p-Coumaric Acid (7400-08-0) → mirabegron coumarate

Conditions	Yield
In methanol at 20℃; for 2h;	94.4%

Hippuric Acid (495-69-2) + (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) → mirabegron hippurate

Conditions	Yield
In methanol at 20℃; for 2h;	93.2%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + (2E)-but-2-enedioic acid (110-17-8) → mirabegron fumarate

Conditions	Yield
In methanol at 20℃; for 2h;	93%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + (2E)-but-2-enedioic acid (110-17-8) → C21H24N4O2S*C4H4O4

Conditions	Yield
In methanol at 15 - 40℃; for 7.83333h;	90%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + n-tetradecanoic acid (544-63-8) → mirabegron myristate

Conditions	Yield
In methanol at 20℃; for 2h;	89.2%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + oxalic acid (144-62-7) → (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide oxalate

Conditions	Yield
In 2-methyltetrahydrofuran at 20 - 25℃; for 1h;	88%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + citric acid (77-92-9) → C21H24N4O2S*C6H8O7

Conditions	Yield
In methanol at 15 - 40℃; for 7.83333h;	88%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + L-Pyroglutamic acid (98-79-3) → 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide L-pyroglutamic acid

Conditions	Yield
In methanol at 15 - 40℃; for 7.83333h;	86%
In methanol; acetone at 20℃; for 1h;	4.2 g

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) → mirabegron phosphate

Conditions	Yield
With phosphoric acid In methanol at 20℃; for 2h;	83.9%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + benzoic acid (65-85-0) → (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide benzoate

Conditions	Yield
In 2-methyltetrahydrofuran at 20 - 25℃; for 1h;	83%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + tartaric acid (87-69-4) → (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide monotartrate

Conditions	Yield
In 2-methyltetrahydrofuran at 20 - 25℃; for 1h;	83%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) → (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenyl)ethylamino]ethyl}acetamide magnesium chloride

Conditions	Yield
With magnesium(II) chloride hexahydrate In butan-1-ol at 85℃; for 0.25h; Solvent;	79.5%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + orotic acid (65-86-1) → mirabegron orotate

Conditions	Yield
In methanol at 20℃; for 2h;	79.2%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + succinic acid (110-15-6) → (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide monosuccinate

Conditions	Yield
In 2-methyltetrahydrofuran at 20 - 25℃; for 1h;	79%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) + toluene-4-sulfonic acid (104-15-4) → (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide p-toluenesulfonate

Conditions	Yield
In 2-methyltetrahydrofuran at 20 - 40℃; for 1.5h;	70%

(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (223673-61-8) → (R)-2-(4-(2-(2-aminothiazol-4-yl)ethylamino)phenethylamino)-1-phenylethanol (1376616-22-6)

Conditions	Yield
Stage #1: (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide With borane-THF In tetrahydrofuran at 0 - 50℃; for 2h; Stage #2: With hydrogenchloride In tetrahydrofuran; water Stage #3: With sodium hydroxide In tetrahydrofuran; water pH=10;	9%
Stage #1: (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide With borane-THF In tetrahydrofuran at 0 - 50℃; for 2h; Stage #2: With sodium carbonate In water	9%

Upstream product

• 29676-71-9 2-amino-4-thiazoleacetic acid 
• 521284-22-0 (R)-2-[ [2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride 
• 391901-45-4 YM-208876 
• 66659-20-9 2-(2-aminothiazol-4-yl)acetic acid hydrochloride 
• 1233249-35-8 4-tert-butoxycarbonylaminophenylacetonitrile 
• 457631-44-6 4-(2-aminoethyl)-N-(tert-butoxycarbonyl)phenylamine 
• 555-21-5 4-Nitrophenylacetonitrile 
• 140-29-4 phenylacetonitrile 
• 3544-25-0 p-aminophenylacetonitrile 
• 782441-52-5 [2-(formylamino)-1,3-thiazol-4-yl]acetyl chloride 
• 75890-68-5 [2-(formylamino)-1,3-thiazol-4-yl]acetic acid 
• 785723-55-9 (2-amino-1,3-thiazol-4-yl)acetyl chloride 
• 611-71-2 (R)-Mandelic Acid 
• 521284-19-5 (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide 

Downstream Products

• 1365244-67-2 YM-538859 
• 1365244-68-3 YM-554028 
• 391901-45-4 YM-208876 

Relevant articles and documents

Preparation method of mirabegron key intermediate

The invention provides a preparation method of a mirabegron key intermediate, namely, a compound as shown in a formula (III). The method is simple, convenient and safe to operate, free of harsh reaction conditions, high in reaction purity and yield and low in process cost which is about 40% of that of a process using a metal catalyst such as palladium carbon, is suitable for large-scale production and conforms to the green chemistry principle. A finished product of mirabegron continues to be prepared by using the intermediate compound as shown in the formula (III) prepared by the method so as to meet the existing requirements.

A new process for the preparation of (R)-2-((4-Aminophenethyl)amino)-1-phenylethanol

The present invention relates to a process for the preparation (R)-2 - ((4-aminophenethyl) amino) -1 - phenylethanol, which is an intermediate of mirabberone intermediate. A manufacturing method of a high purity and high yield amide derivative is provided to produce an amide derivative having high purity and high yield without using a specific purification process by using a zinc powder reduction catalyst.

Mirabegron impurity compound, and preparation method and application thereof

The invention discloses a mirabegron impurity compound, and a preparation method and application thereof. The mirabegron impurity compound disclosed by the invention is relatively high in purity and can be used as a reference substance for effectively identifying impurities generated in mirabegron synthesis, so that the drug quality of mirabegron is controlled.

Preparation method of mirabegron (by machine translation)

The method is convenient to operate, controllable in reaction process, high in 2 - final product purity,4 - high in yield and suitable for industrial production, so that a more valuable synthesis route is provided for preparing mirabead, good social benefits and economic benefits can be brought, and the economic value potential is great. (by machine translation)

Preparation method of mirabegron

The invention discloses a preparation method of mirabegron, and the method comprises: S1, carrying out reduction reaction on p-nitrophenylacetonitrile to obtain p-nitrophenylacetaldehyde; S2, carryingout condensation reduction on the p-nitrophenylacetaldehyde and (R) 2-amino-1-phenethyl alcohol to obtain (R) 2-(4-nitrophenethyl) amino)-1-phenyl ethyl alcohol; S3, carrying out reduction on the (R)2-amino-1-phenethyl alcohol to obtain (R) 2-(4-nitrophenethyl) amino)-1-phenyl ethyl alcohol to obtain an intermediate (R) 2-((4-aminophenyl ethyl) amino)-1-phenyl ethyl alcohol; and S4, carrying outcondensation on the (R) 2-((4-aminophenyl ethyl) amino)-1-phenyl ethyl alcohol and aminothiazole acetic acid to obtain the mirabegron. According to the method, the starting raw materials are cheap and easy to obtain, the reaction conditions are controllable, the synthetic route steps are few, the yield is high, the cost is low, and the prepared mirabegron is high in purity.

Salts of amide derivatives and method for preparing the same

In the present invention, a cyclised amino acid is disclosed as an aliphatic or aromatic disulfonate or lactam structure, which is a salt of an amide derivative represented by chemical formula 1. The salt of the amide derivative does not absorb moisture, and is stable and has excellent solubility in water. In chemical formula 1, the B ring is a substituted or unsubstituted heteroaryl group, X is a bond, hydroxy, lower alkylene, lower alkenylene, carbonyl or -NH-, and A is lower alkylene or -lower alkylene-O-.COPYRIGHT KIPO 2019

Method for preparing amide derivatives

Disclosed in the present specification is a method for producing amide derivatives of chemical formula 1. The method comprises the steps of: conducting a reaction of chemical formula 2 and chemical formula 3; and reacting chemical formula 4 with a compound produced by the reaction. By using the method disclosed in the present specification, it is possible to exclude a hydrogenation reaction which is limited by high production cost and low production yield in on-site production.COPYRIGHT KIPO 2018

Synthetic method of the compound

A synthesis method of a compound shown as a formula 1 is provided. The method includes (1) bringing a compound shown as a formula 2 into contact with compound shown as a formula 3 to produce a compound shown as a formula 4; (2) subjecting nitro of the compound shown as the formula 4 to a reduction reaction to produce a compound shown as a formula 5; and (3) bringing the compound shown as the formula 5 into contact with a compound shown as a formula 6 to produce the compound shown as the formula 1. The method is short in route. Initial raw materials are cheap and easily available. All the intermediates are easy to purify and simple in after-treatment. The product is high in purity and high in yield. The method benefits industrial production.

Study on a New Method for Synthesis of Mirabegron

Mirabegron is a muscle relaxing drug for the treatment of overactive bladder. The existing synthetic methods for mirabegron produced intermediate product 4-(2-(phenethylamino)ethyl)aniline, which complicated the final product purification process. In this study, we designed a new synthetic route for mirabegron with low cost starting materials and a production of mirabegron at a 99.6% purity and a 61% overall yield. Particularly, this new synthetic route did not produce side product 4-(2-(phenethylamino)ethyl)aniline, which significantly simplified the product purification process.

First Direct Isolation of Stable α-Form Crystals of Mirabegron, a Selective β3-Adrenoceptor Agonist

An efficient and scalable method for the direct isolation of stable α-form crystals of Mirabegron (1) is developed. The developed method negates transformation of metastable β-form crystals into α-form crystals thereby overcoming the limitations of reported methods and avoids additional processing steps during its manufacture. The developed method directly provides stable α-form crystals of Mirabegron (1) with yield of around 84% and purity of >99.77% by HPLC in a single step.