312753-06-3

Usage

Indication

Indacaterol is used in the maintenance of airflow obstruction in individuals with COPD for the long term, including emphysema and chronic bronchitis.

Mechanism of Action

By stimulating the adrenergic beta-2-receptors in the airways’ smooth muscles, indacaterol is able to cause relaxation, thus augmenting the diameter of the airways that are normally constricted in COPD and asthma. Because of its high affinity to the lipid draft domains in the membrane of the airways, it is long acting, therefore it slowly detaches from the receptors. It is rapid acting due to its high intrinsic characteristic.

Toxicity

In case of an overdose of indacaterol, the expected signs and symptoms include excessive beta-adrenergic stimulation, hypotension, hypertension, nervousness, fatigue, hyperglycaemia, insomnia, and metabolic acidosis.

Originator

Novartis (United Kingdom)

Side effects

The most commonly reported adverse events associated with indacaterol treatment were nasopharyngitis, upper respiratory tract infection, and headache and cough following inhalation. Adverse events were mild or moderate in most cases, and became less frequent with continued treatment.

Synthesis

The chemical synthesis of indacaterol begins with a-chlorination of 5-acetyl-8-benzyloxy-2-quinolone with benzyltrimethylammonium dichloro-iodate. The resultant chloroketone is reduced with borane in tetrahydrofuran in the presence of the chiral boron catalyst R-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2c][ 1,3,2]oxazaborole to produce the corresponding chlorohydrin intermediate in high enantiomeric excess. The chlorohydrin intermediate is cyclized to the corresponding epoxide by treatment with potassium carbonate, the epoxide is condensed with 5,6-diethylindan-2-amine, and the benzyl protecting group is removed by hydrogenolysis to produce indacaterol. The 5,6-diethylindan-2-amine intermediate is derived from 1,2-diethylbenzene via Friedel-Crafts acylation with 3-chloropropionyl chloride, cyclization of the resultant 3-chloro- 1-(3,4-diethylphenyl)-1-propanone by means of concentrated sulfuric acid to 5,6-diethylindan-1-one, oximation with butyl nitrite, and reduction of the oxime to an amine via treatment with hydrogen over palladium- carbon.

InChI:InChI=1/C24H28N2O3/c1-3-14-9-16-11-18(12-17(16)10-15(14)4-2)25-13-22(28)19-5-7-21(27)24-20(19)6-8-23(29)26-24/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29)

Synthetic route

indacaterol maleate → indacaterol (312753-06-3)

Conditions	Yield
With lithium hydroxide monohydrate In methanol at 35℃; for 1h; Reagent/catalyst;	99.84%

(R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-indole-2-yl)amino]-1-hydroxyethyl]quinolin-2(1H)-one (435273-75-9) → indacaterol (312753-06-3)

Conditions	Yield
Stage #1: (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-indole-2-yl)amino]-1-hydroxyethyl]quinolin-2(1H)-one With 5%-palladium/activated carbon; hydrogen In ethanol at 20℃; for 2h; Stage #2: With 5%-palladium/activated carbon; hydrogen In ethanol at 40℃; under 757.576 Torr; for 4h;	97%
With 5%-palladium/activated carbon; hydrogen; acetic acid In methanol at 20℃;	85%
With palladium 10% on activated carbon; hydrogen In methanol at 19 - 22℃; for 1h; Inert atmosphere;	83%

5-[(1R)-2-[N-benzyl-(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-(benzyloxy)-2(1H)-quinolone → indacaterol (312753-06-3)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; acetic acid In methanol at 20℃;	86.2%
With palladium 10% on activated carbon; hydrogen; acetic acid at 40℃; under 15201 Torr; Pressure; Reagent/catalyst; Temperature;

(R)-5- [2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one hydrochloride → indacaterol (312753-06-3)

Conditions	Yield
With palladium on activated charcoal; hydrogen; acetic acid In methanol at 25 - 30℃; under 2250.23 - 3000.3 Torr; for 4h;	85.5%

5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-triethylsilyloxyethyl]-8-(benzyloxy)-2(1H)-quinolone → indacaterol (312753-06-3)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; acetic acid; tetra-n-butylammoniumfluoride trihydrate In methanol at 20℃;	84.5%

5-[(1R)-2-[N-benzyl-(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-triethylsilyloxyethyl]-8-(benzyloxy)-2(1H)-quinolone → indacaterol (312753-06-3)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; acetic acid; tetra-n-butylammoniumfluoride trihydrate In methanol at 20℃;	83.7%

8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-one tartrate (753498-33-8) → indacaterol (312753-06-3)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol under 225.023 Torr; Inert atmosphere;	77%
With 5%-palladium/activated carbon; hydrogen In methanol under 225.023 Torr; Inert atmosphere;	77%

5-{2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl}-8-hydroxy-1H-quinolin-2-one → indacaterol (312753-06-3)

Conditions	Yield
With triethylamine In ethanol; hexane at 25℃; Resolution of racemate;	49%

(R)-5- [2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one benzoic acid salt → indacaterol (312753-06-3)

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In acetic acid for 2 - 8h;
With hydrogen; 5%-palladium/activated carbon In acetic acid for 2 - 8h;

5,6-diethyl-2,3-dihydro-1H-inden-2-amine (312753-70-1) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid; -butyl vinyl ether / tetrahydrofuran; toluene / 0.5 h / 20 - 25 °C / Molecular sieve 1.2: 100 °C 2.1: 5%-palladium/activated carbon; hydrogen / methanol / 225.02 Torr / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 20 °C 1.2: 16 h / 0 - 20 °C 2.1: Chiralcel AS-V / aq. phosphate buffer; acetonitrile / 25 °C / Resolution of racemate 3.1: 5%-palladium/activated carbon; hydrogen / ethanol / 2 h / 20 °C 3.2: 4 h / 40 °C / 757.58 Torr View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 20 °C 1.2: 16 h / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / ethanol / 8 h / 20 - 40 °C / 757.58 Torr 3.1: triethylamine / ethanol; hexane / 25 °C / Resolution of racemate View Scheme
Multi-step reaction with 4 steps 1: sodium cyanoborohydride / ethanol / 4 h / -25 - 80 °C / Inert atmosphere 2: sodium carbonate; potassium iodide / acetonitrile / 24 h / -25 - 80 °C 3: (-)-diisopinocamphenylborane chloride / dichloromethane; tetrahydrofuran / 25 h / 10 - 20 °C 4: hydrogen; acetic acid; palladium 10% on activated carbon / 40 °C / 15201 Torr View Scheme
Multi-step reaction with 4 steps 1: butan-1-ol / 3 h / 100 - 110 °C 2: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 0 - 3 °C / Inert atmosphere 3: potassium carbonate / water; methanol / 1 h 4: acetic acid; palladium 10% on activated carbon; hydrogen / methanol / 6 h / 0 - 8 °C / 750.08 - 1500.15 Torr / Inert atmosphere View Scheme

8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one (530084-79-8) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid; -butyl vinyl ether / tetrahydrofuran; toluene / 0.5 h / 20 - 25 °C / Molecular sieve 1.2: 100 °C 2.1: 5%-palladium/activated carbon; hydrogen / methanol / 225.02 Torr / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: 1H-imidazole / chloroform / 10 h / 25 °C / Reflux 2.1: 1-methyl-pyrrolidin-2-one / 12 h / 95 - 100 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 50 - 55 °C 3.2: 1 h / 25 - 30 °C 4.1: acetic acid; palladium on activated charcoal; hydrogen / methanol / 4 h / 25 - 30 °C / 2250.23 - 3000.3 Torr View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 90 °C 2.1: hydrazine hydrate / ethanol / 6 h / Reflux 2.2: 80 °C 3.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 4.1: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

5-(2,2-Dihydroxyacetyl)-8-(benzyloxy)-carbostyril (100331-91-7) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 20 °C 1.2: 16 h / 0 - 20 °C 2.1: Chiralcel AS-V / aq. phosphate buffer; acetonitrile / 25 °C / Resolution of racemate 3.1: 5%-palladium/activated carbon; hydrogen / ethanol / 2 h / 20 °C 3.2: 4 h / 40 °C / 757.58 Torr View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 20 °C 1.2: 16 h / 0 - 20 °C 2.1: 5%-palladium/activated carbon; hydrogen / ethanol / 8 h / 20 - 40 °C / 757.58 Torr 3.1: triethylamine / ethanol; hexane / 25 °C / Resolution of racemate View Scheme

5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-(1H)-quinolin-2-one → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5%-palladium/activated carbon; hydrogen / ethanol / 8 h / 20 - 40 °C / 757.58 Torr 2: triethylamine / ethanol; hexane / 25 °C / Resolution of racemate View Scheme

8-benzyloxy-5-(2-bromoacetyl)-1H-quinolin-2-one (100331-89-3) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; dimethylsulfide borane complex / tetrahydrofuran / 0 - 30 °C / Inert atmosphere 1.2: 0 - 30 °C 2.1: 1H-imidazole / chloroform / 10 h / 25 °C / Reflux 3.1: 1-methyl-pyrrolidin-2-one / 12 h / 95 - 100 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 50 - 55 °C 4.2: 1 h / 25 - 30 °C 5.1: acetic acid; palladium on activated charcoal; hydrogen / methanol / 4 h / 25 - 30 °C / 2250.23 - 3000.3 Torr View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: 1.33 h / 50 °C 2.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / dichloromethane; toluene; tetrahydrofuran / 2 h / -10 °C 3.1: hydrazine hydrate / ethanol / 6 h / Reflux 3.2: 80 °C 4.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 5.1: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

(R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one (530084-74-3) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-methyl-pyrrolidin-2-one / 12 h / 95 - 100 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 50 - 55 °C 2.2: 1 h / 25 - 30 °C 3.1: acetic acid; palladium on activated charcoal; hydrogen / methanol / 4 h / 25 - 30 °C / 2250.23 - 3000.3 Torr View Scheme

(R)-8-(benzyloxy)-5-[1-((tert-butyldimethylsilyl)oxy)-2-((5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino)ethyl]quinolin-2(1H)-one → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 50 - 55 °C 1.2: 1 h / 25 - 30 °C 2.1: acetic acid; palladium on activated charcoal; hydrogen / methanol / 4 h / 25 - 30 °C / 2250.23 - 3000.3 Torr View Scheme

N-benzyl-5,6-diethyl-2,3-dihydro-1H-inden-2-amine (312753-79-0) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium carbonate; potassium iodide / acetonitrile / 24 h / -25 - 80 °C 2: (-)-diisopinocamphenylborane chloride / dichloromethane; tetrahydrofuran / 25 h / 10 - 20 °C 3: hydrogen; acetic acid; palladium 10% on activated carbon / 40 °C / 15201 Torr View Scheme
Multi-step reaction with 2 steps 1: triethylamine; sodium iodide / N,N-dimethyl-formamide / 3 h / 20 °C 2: acetic acid; 5%-palladium/activated carbon; hydrogen; tetra-n-butylammoniumfluoride trihydrate / methanol / 20 °C View Scheme

5-{2-[N-benzyl(5,6-diethyl-2,3-dihydro-1H-indan-2-yl)amino]acetyl}-8-(benzyloxy)-1H-quinolin-2-one → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: (-)-diisopinocamphenylborane chloride / dichloromethane; tetrahydrofuran / 25 h / 10 - 20 °C 2: hydrogen; acetic acid; palladium 10% on activated carbon / 40 °C / 15201 Torr View Scheme

8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one (530084-79-8) + 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (312753-70-1) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; sodium iodide / N,N-dimethyl-formamide / 3 h / 20 °C 2: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol / 20 °C View Scheme

8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one (530084-79-8) + N-benzyl-5,6-diethyl-2,3-dihydro-1H-inden-2-amine (312753-79-0) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; sodium iodide / N,N-dimethyl-formamide / 3 h / 20 °C 2: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol / 20 °C View Scheme

Reaxys ID: 32936244 → indacaterol (312753-06-3)

Reaxys ID: 32936246 → indacaterol (312753-06-3)

Reaxys ID: 32936247 → indacaterol (312753-06-3)

2-chloro-5,6-diethylindan → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 2: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

5-(2-phthalimido-1-oxo-ethyl)-8-phenylmethoxy-(1H)-quinolin-2-one → indacaterol (312753-06-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / dichloromethane; toluene; tetrahydrofuran / 2 h / -10 °C 2.1: hydrazine hydrate / ethanol / 6 h / Reflux 2.2: 80 °C 3.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 4.1: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

5-(R)-(2-amino-1-hydroxy-ethyl)-8-phenylmethoxy-(1H)-quinolin-2-one (774222-23-0) → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 2: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

5-(R)-(2-phthalimido-1-hydroxy-ethyl)-8-phenylmethoxy-(1H)-quinolin-2-one → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrazine hydrate / ethanol / 6 h / Reflux 1.2: 80 °C 2.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 3.1: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

5-acetyl-8-hydroxy-2(1H)-quinolinone (62978-73-8) → indacaterol (312753-06-3)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: boron trifluoride diethyl etherate / dichloromethane / 0.17 h / 0 °C 2.2: 2.75 h / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 1.33 h / 50 °C 4.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / dichloromethane; toluene; tetrahydrofuran / 2 h / -10 °C 5.1: hydrazine hydrate / ethanol / 6 h / Reflux 5.2: 80 °C 6.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 7.1: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

5-acetyl-8-benzyloxy-1H-quinolin-2-one (93609-84-8) → indacaterol (312753-06-3)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: boron trifluoride diethyl etherate / dichloromethane / 0.17 h / 0 °C 1.2: 2.75 h / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 °C 2.2: 1.33 h / 50 °C 3.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / dichloromethane; toluene; tetrahydrofuran / 2 h / -10 °C 4.1: hydrazine hydrate / ethanol / 6 h / Reflux 4.2: 80 °C 5.1: N-ethyl-N,N-diisopropylamine; sodium iodide / N,N-dimethyl-formamide / 20 - 90 °C 6.1: acetic acid; 5%-palladium/activated carbon; hydrogen / methanol View Scheme

C31H34N2O3*BrH → indacaterol (312753-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / water; methanol / 1 h 2: acetic acid; palladium 10% on activated carbon; hydrogen / methanol / 6 h / 0 - 8 °C / 750.08 - 1500.15 Torr / Inert atmosphere View Scheme

indacaterol (312753-06-3) + succinic acid (110-15-6) → Indacaterol succinate

Conditions	Yield
In isopropyl alcohol at 20 - 80℃; for 18.0833h;	96.3%

indacaterol (312753-06-3) + malonic acid (141-82-2) → Indacaterol malonate

Conditions	Yield
In butan-1-ol at 20 - 80℃; for 18.25h;	95.28%

indacaterol (312753-06-3) + toluene-4-sulfonic acid (104-15-4) → Indacaterol tosylate

Conditions	Yield
In ethyl acetate at 20 - 60℃;	94.8%

indacaterol (312753-06-3) + acetic acid (64-19-7) → Indacaterol acetate

Conditions	Yield
In dichloromethane; ethyl acetate; isopropyl alcohol at 5 - 35℃; for 11h; Temperature; Solvent;	93.73%
In isopropyl alcohol at 20 - 80℃; for 17h;	84.9%

indacaterol (312753-06-3) + maleic acid (110-16-7) → indacaterol maleate

Conditions	Yield
In isopropyl alcohol for 1h; Reflux;	92.5%
In ethanol at 60℃; for 0.166667h;	83%
In ethanol at 50 - 60℃;

indacaterol (312753-06-3) + methanesulfonic acid (75-75-2) → Indacaterol mesylate

Conditions	Yield
In water at 20 - 70℃; for 20.2h;	86.9%

indacaterol (312753-06-3) → Indacaterol sulfate

Conditions	Yield
With sulfuric acid; acetic acid at 20 - 50℃; for 18.0833h;	86.9%

indacaterol (312753-06-3) + (2E)-but-2-enedioic acid (110-17-8) → (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one fumarate

Conditions	Yield
In methanol at 20 - 50℃; for 3.33333h;	86.4%

indacaterol (312753-06-3) + L-Tartaric acid (87-69-4) → (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one L-tartrate

Conditions	Yield
In isopropyl alcohol at 50℃; for 15h;	84.27%

indacaterol (312753-06-3) → Indacaterol hydrochloride

Conditions	Yield
With hydrogenchloride In methanol at 20 - 50℃; for 17h;	84.27%

indacaterol (312753-06-3) → Indacaterol hydrobromide

Conditions	Yield
With hydrogen bromide In methanol at 20 - 50℃; for 3.25h;	84.27%

indacaterol (312753-06-3) + formic acid (64-18-6) → Indacaterol formate

Conditions	Yield
In methanol at 25 - 50℃; for 15h;	79.37%

indacaterol (312753-06-3) + 1-hydroxy-2-naphthoic acid (86-48-6) → (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one xinafoate

Conditions	Yield
In butan-1-ol at 20 - 100℃; for 17h;	76%

indacaterol (312753-06-3) + Hippuric Acid (495-69-2) → (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hippurate

Conditions	Yield
In methanol at 20 - 50℃; for 4.16667h;	75.7%

indacaterol (312753-06-3) + glycolic Acid (79-14-1) → (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one glycolate

Conditions	Yield
In methanol at 20 - 50℃;	71.37%

indacaterol (312753-06-3) + ethanesulfonic acid (594-45-6) → (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one esylate

Conditions	Yield
In water; dimethyl sulfoxide at 20 - 50℃;

indacaterol (312753-06-3) → [Br]QAB149

Conditions	Yield
With bromine In acetic acid at 20℃; for 1h;

indacaterol (312753-06-3) → [3H]QAB149

Conditions	Yield
Multi-step reaction with 2 steps 1: bromine / acetic acid / 1 h / 20 °C 2: palladium 10% on activated carbon; tritium; triethylamine / 5 h / 20 °C View Scheme

indacaterol (312753-06-3) → C24H30N2O3 (1403389-05-8)

Conditions	Yield
With 10% Pd/C; hydrogen at 25℃; under 760.051 Torr; for 360h;

indacaterol (312753-06-3) → C24H27ClN2O2

Conditions	Yield
With thionyl chloride In acetonitrile for 0.0833333h; Reflux;

indacaterol (312753-06-3) → 5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-one

Conditions	Yield
Multi-step reaction with 2 steps 1.1: thionyl chloride / acetonitrile / 0.08 h / Reflux 2.1: sodium tetrahydroborate / ethanol / 18 h / 25 °C 2.2: 2 h / Reflux View Scheme

Upstream product

• 435273-75-9 (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-indole-2-yl)amino]-1-hydroxyethyl]quinolin-2(1H)-one 
• 312753-70-1 5,6-diethyl-2,3-dihydro-1H-inden-2-amine 
• 753498-33-8 8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-one tartrate 
• 530084-79-8 8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one 
• 100331-91-7 5-(2,2-Dihydroxyacetyl)-8-(benzyloxy)-carbostyril 
• 100331-89-3 8-benzyloxy-5-(2-bromoacetyl)-1H-quinolin-2-one 
• 530084-74-3 (R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one 
• 312753-79-0 N-benzyl-5,6-diethyl-2,3-dihydro-1H-inden-2-amine 
• 774222-23-0 5-(R)-(2-amino-1-hydroxy-ethyl)-8-phenylmethoxy-(1H)-quinolin-2-one 
• 62978-73-8 5-acetyl-8-hydroxy-2(1H)-quinolinone 
• 93609-84-8 5-acetyl-8-benzyloxy-1H-quinolin-2-one 

Downstream Products

• 753498-25-8 indacaterol maleate 
• 753498-25-8 (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one fumarate 

Relevant academic research and scientific papers

Preparation method for indacaterol acetate

The invention provides a preparation method for indacaterol acetate. The method has a simple preparation process, a small discharge amount of three waste (wastewater, waste gas and solid waste), low preparation costs, a higher yield and higher product purity, is conducive to large-scale commercial production, and has higher economic value; and the crystal form of the target product obtained by themethod is consistent with that reported in a literature, and the crystal form is characterized by a characteristic absorption peak of an X-ray diffraction pattern.

A maleic acid yin dutrow intermediate and its preparation and use

The invention relates to maleic acid yin dutrow intermediate (R)- 8 - (benzyloxy) - 5 - [2 - [(5, 6 - diethyl - 2, 3 - dihydro - 1 H - indene - 2 - yl) amino] - 1 - hydroxy ethyl] quinoline - 2 (1 H) - one a new salt and its crystalline form, the salt and its crystalline form has good impurity removing effect and thermodynamic stability, the preparation method is simple, the operation is facilitated and the storage, is suitable for industrial application. The invention also relates to the new salt and its crystal preparation method, and process for the preparation of maleic acid yin dutrow use.

A Process for Preparing Indacaterol and Salts Thereof

The present invention relates to a process for preparing indacaterol or salts thereof. The process comprises of forming compound of Formula 1 by reacting compound of Formula 2 and compound of Formula 3 in the presence of a solvent to Form compound of Formula 4, which on removal of the protecting groups forms compound of Formula 1.

Preparation method for indacaterol maleate

The invention specifically relates to a preparation method for indacaterol maleate, belonging to the field of drug synthesis. The preparation method is simple and short in steps, easy to operate, safe, friendly to environment and fee of an alkaline solution; after a heating reaction, a coupled product in the step 1) can be obtained, and the amount of produced regioisomers, dimers and other by-products is small; the yield of the product indacaterol maleate is high, as high as 93%, and the HPLC purity of the product indacaterol maleate is more than 97.8%; post-treatment is simple, and industrialproduction of indacaterol maleate is facilitated; and the product indacaterol maleate is high in optical purity.

Preparation method for indacaterol or salt thereof

The invention relates to a preparation method for indacaterol or a salt thereof. According to the method, hydrogen diluted by inert gas is selected and used as a hydride source, and high-purity indacaterol maleate is prepared under metal catalysis conditions.

A new method of [...]dutrow

The present invention discloses a new method for synthesizing indacaterol. The present invention provides a completely-new indacaterol synthesis method. Compared with the known method in the prior art, the method of the present invention has the following characteristics that: the easily available starting raw material is adopted, the side reaction is less when the two raw material fragments dock, the reaction conditions of the route are mild, the route is short, the yield is high, and the market competitiveness is provided.

Novel Process for Preparation of Indacaterol or Its Pharmaceutically Acceptable Salts

A novel process the for preparation of Indacaterol or its pharmaceutically acceptable salts and novel intermediates employed in the preparation thereof that is economically significant for large scale.

dutrow[...][...] method for the synthesis of intermediates

Disclosed is an intermediate for synthesizing indacaterol, having a structure represented by formula IV. Also disclosed are a method for synthesizing the indacaterol intermediate and a method for synthesizing indacaterol by using the intermediate. During synthesis of indacaterol, the intermediate of formula IV is reduced to obtain a chiral or racemic compound, which is then debenzylated to obtain indacaterol or a raceme thereof. By using the compound of formula IV as an intermediate for synthesizing indacaterol, the present invention provides a new route for synthesizing indacaterol, and avoids various byproducts produced in the process of synthesizing indacaterol using conventional methods.

A METHOD FOR THE PREPARATION OF 5-[(R)-2-(5,6-DIETHYL-INDAN-2-YLAMINO)-L-HYDROXYETHYL]- 8-HYDROXY-(1H)-QUINOLIN-2-ONE (INDACATEROL)

The invention relates to a new method of synthesis of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)- 1-hydroxyethyl]-8-hydroxy-(1H)-quinolin-2-one of formula (R)-2, known under the generic name indacaterol, which is used for the treatment of chronic obstructive pulmonary disease (COPD). The method comprises preparation of the racemic intermediate 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-(1H)-quinolin-2-one of formula 1, which is further, in an arbitrary order, chirally resolved and debenzylated, and subsequently indacaterol of formula (R)-2 is isolated.

METHODS FOR THE PREPARATION OF INDACATEROL AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The invention relates to new and improved processes for the preparation of Indacaterol and pharmaceutically acceptable salts thereof as well as intermediates for the preparation of Indacaterol. The new process avoids the use of the epoxide compound known in the art and the impurities associated therewith and results in a higher yield.